the janus kinase - signal transducer and activator of transcription ( jak - stat ) signaling pathway was first characterized in the early 1990s . four jak and seven stat genes have been found in humans , one jak and one stat in drosophila and four stats but no jaks in dictyostelium . binding of extracellular ligands to transmembrane receptors induces the receptors to dimerize and to activate jaks associated with these receptors . the activated jaks phosphorylate tyrosine residues on the cytoplasmic tails of the receptors , which function as docking sites for cytoplasmic stat proteins . the stats are then phosphorylated on a critical tyrosine residue by the activated jaks ; once phosphorylated , the stats dimerize and move to the nucleus , where they activate transcription of particular genes . the simplicity of the drosophila system , with only one jak and one stat gene , has made it an excellent model system for studying this pathway . canonical jak - stat signaling is involved in many aspects of development and physiology by virtue of its direct transcriptional regulation of target genes . it turns out , however , that jak and stat function in non - canonical modes as well , in both flies and mammals . stat1 , stat3 , stat5 , and stat6 have been reported to function non - canonically in mammals . in 1997 showed that stat1 is required for tnf plus actinomycin induced apoptosis of cultured mammalian cells . cells deficient in stat1 were resistant to apoptosis , but sensitivity was restored by wild - type stat1 or a stat1 variant unable to dimerize . the authors inferred from the results with the stat1 variant that stat1 might be functioning non - canonically under these circumstances . several non - canonical functions have been attributed to stat3 . in 2000 , wang et al . published data showing that a src inhibitor prevents the activation of stat3 by pdgf and pdgfr in balb / c-3t3 cells , suggesting that stat3 is activated by src kinase in this case . in 2004 , silver et al . reported the results of immunostaining experiments indicating that phosphorylated stat3 localizes to focal adhesions , in addition to its nuclear localization ; furthermore , stat3 was co - immunoprecipitated with focal adhesion molecules such as paxillin and focal adhesion kinase . in 2006 , ng et al . described a physical interaction between the microtubule binding protein stathmin and stat3 . in cells without stat3 , microtubules were disrupted ; in cells with stat3 , microtubules were not disrupted , and a physical interaction between stat3 and stathmin was demonstrated by immunoprecipitation . transfection of cultured cells with stat3 attenuated stathmin inhibition of microtubule polymerizaton , as did addition of stat3 to an in vitro microtubule assembly assay containing stathmin . thus , by binding to stathmin , stat3 apparently prevents stathmin binding to microtubules , and promotes microtubule polymerization . localized stat3 to a subcellular mitochondrial fraction via western blots , and found by means of immunoprecipitation that stat3 is associated with electron transport chain complex i. respiration rates were substantially reduced in mitochondria from cells lacking stat3 , but were restored in mitochondria from stat / stat cells had been reconstituted with wild - type stat3 or with a stat3 construct targeted only to mitochondria . moreover , using mutant stat3 constructs targeted to mitochondria , wegrzyn et al . found that neither stat3 phosphorylation at tyr nor dna binding nor dimerization was required for restoration of normal respiration rates , though phosphorylation of ser was required . substantiated that stat3 is found in the mitochondrial fraction ; in addition , they showed mitochondrial stat to be insensitive to proteinase k treatment in the absence of detergent , corroborating that stat3 was inside of mitochondria . using procedures similar to those of wegrzyn et al . , they found that neither stat3 phosphorylation at tyr nor dna binding nor dimerization was required for its role in ras transformation , though ser phosphorylation was required . gough et al . also reported that loss of stat3 resulted in defects in electron transport chain function , though there were some differences between the two reports regarding the particular complexes affected . in 2012 , lee et al . reported the results of immunostaining experiments indicating that stat5a and stat5b are localized to the golgi apparatus in digitonin - permeabilized human pulmonary arterial endothelial cells ( dp - hpaec ) . gfp - tagged stat5a appeared to localize to the golgi apparatus . in 2013 , lee et al . reported the localization of stat5a to endoplasmic reticulum ( er ) sheets in dp - hpeac ; immunoblots with cell extracts showed an association of stat5a with two er proteins deleterious effects on the endoplasmic reticulum were observed when stat5 was knocked down by means of anti - stat5 sirna . these effects were seen in enucleated as well as nucleated cells , suggesting that stat5 might be functioning non - canonically in the er . in 2013 , sehgal described an association of stat6-gfp , but not stat3 , with mitochondria in dp - hpaec and digitonin - permeabilized human pulmonary smooth muscle cells . non - canonical functions have been demonstrated for jak2 , as well . in 2006 , nilsson et al . reported that prolactin increases stability of the nf1-c2 transcription factor in a mouse mammary epithelial cell line . using a jak inhibitor , they determined that this stabilizing effect requires jak2 ; this result was confirmed when jak2 levels were decreased with a jak2-sp.ecific sirna . western blot analysis indicated that phosphorylated jak2 was present in the nucleus of these cells as well as the nuclei of three human breast cancer cell lines , and that nf1-c2 is associated with jak in the nucleus . using an in vitro proteasome assay and a jak inhibitor , it was determined that the association of jak2 with nf1-c2 prevents its degradation . in 2009 , dawson et al . demonstrated with immunostaining , as well as subcellular fractionation and western blotting , that jak2 can be found in the nuclei of human hematopoietic cells . using an in vitro kinase assay followed by western blotting , they showed that jak2 phosphorylates histone h3 at tyr 41 . consistent with these results , when a hematopoietic cell line was incubated with jak2 inhibitors there was a loss of h3y41 phosphorylation . an unmodified h3 peptide encompassing amino acids 3156 was found to bind heterochromatin protein 1 ( hp1 ) in vitro , and this binding was significantly decreased when the y41 residue was phosphorylated . the biological significance of these observations was investigated by immunoprecipitation of chromatin from a hematopoietic cell line . this downregulation correlated with decreased levels of h3y41ph and an increase in hp1 binding at sites surrounding the lmo2 transcriptional start site . in drosophila , a connection between jak - stat signaling and chromatin remodeling has suggested by the observation that the transcriptional repressor ken recruits a nucleosome remodeling factor , nurf , to stat / ken mutual binding sequences to repress stat - mediated transcription . furthermore , the drosophila protein inhibitor of activated stat homolog ( dpias ) is known to be a suppressor of variegation , a heterochromatin - mediated phenomenon . in 2006 , shi et al . published work implicating drosophila jak in the regulation of heterochromatin . the remainder of this review will focus on what has been learned in drosophila about the regulation of heterochromatin by jak and stat . we will also discuss how changes in heterochromatin levels affect the formation of hematopoietic tumor - like masses , genome stability , and lifespan . a constitutively activated jak mutant , hop , causes hematopoietic tumor - like masses in drosophila . the discovery of roles for jak and stat in heterochromatin regulation , began with a genetic screen in drosophila to identify genes which affect the formation of the hematopoietic tumor - like masses induced by hop , that is , genes which modify the hop phenotype . a number of the modifiers identified were genes involved in chromatin modification , including heterochromatin protein 1 ( hp1 ) , the histone h3-k9 methyltransferase su(var)39 , and the histone deacetylase ( hdac ) rpd3 . flies carrying one copy of the activated jak mutant hop and one copy of one of the following loss of function or hypomorphic mutants su(var)205 , su(var)39 , or rpd3showed significantly higher numbers of tumors , though animals carrying a single copy of the su(var)205 , su(var)39 , or rpd3 mutant without hop did not have these masses . hp1 and su(var)39 are essential heterochromatin components that are necessary for heterochromatin - mediated gene silencing . these results raised the question of how a decrease in heterochromatin components promotes an increase in hematopoietic tumors . does jak overactivation actively disrupt hp1/su(var)39 gene silencing , which has been shown to act as a tumor - suppressive mechanism , or is there a competition between overactivated jak and the hp1/su(var)39 silencing system for access to stat target genes that promote tumorigenesis ? to determine whether jak overactivation disrupts heterochromatic gene silencing , shi et al . investigated the phenomenon of position effect variegation ( pev ) , in which active genes normally found in euchromatic regions of the genome can become silenced when placed in conjunction to heterochromatic regions . the silencing occurs in some cells but not in others , in what appears to be a stochastic manner . in drosophila , pev can be evaluated easily by inspecting eye color in appropriate fly strains . in wild - type flies , expression of the euchromatic white gene is required for normal red eye color . however , in certain fly strains , the white gene has been juxtaposed , by genetic inversion , to a heterochromatic region of the genome , resulting in suppression of white expression in some eye cells but not others ; thus , the eyes are red and white , with a variegated appearance . the more heterochromatic gene silencing there is in such fly strains , the more white the eyes appear , while a de - repression of silencing results in more red color . loss - of - function mutations in even a single copy of hp1 or su(var)39 are known to suppress pev , that is , give less heterochromatic gene silencing . shi et al . discovered that the constitutively active hop mutant suppressed pev as well , while loss - of - function jak mutants enhanced pev , suggesting that overactivated jak indeed disrupts heterochromatic gene silencing . shi et al . then assessed more directly the effects of different levels of jak on heterochromatin . salivary glands were immunostained with anti - hp1 and anti - h3mk9 antibodies , and centromeric heterochromatin was examined . in support of the idea that overactivated jak disrupts heterochromatin , shi et al . found that larvae carrying a hop ( jak gain - of - function ) mutation , showed much lower levels of hp1 and h3mk9 at centromeric heterochromatin in comparison with wild - type larvae ; on the other hand , larvae with one jak loss - of - function allele , exhibited increased areas of hp1 and h3mk9 concentration in their nuclei . is the tumorigenesis caused by increased jak activity related to the decrease in heterochromatin ? to address this question , shi et al . even a moderate increase in hp1 levels by means of transgene expression , completely suppressed hop - induced hematopoietic tumor formation . these data strongly suggest that decreased hp1 localization to heterochromatin is required for hop - induced tumorigenesis . thus , a previously unknown function for jak was discovered : the regulation of heterochromatin . shi et al . then asked whether the heterochromatin disruption caused by jak overactivation was mediated by stat . to answer this question , they reduced the levels of stat92e , and once again looked at pev to assess the effect on heterochromatic gene silencing . since reducing levels of jak enhanced heterochromatic gene silencing surprisingly , however , they found that reducing the levels of stat92e caused a significant de - repression of silencing . in support of these surprising results , when stat92e levels were increased by means of a stat92e transgene or a chromosomal duplication , reporter gene expression was completely silenced , that is to say , heterochromatic gene silencing was enhanced . jak activates stat ; higher levels of jak activity lead to more activated stat and higher levels of transcription from stat - activated genes ; but heterochromatic gene silencing is enhanced by higher levels of stat and lower levels of activated jak . shi et al . began to resolve this paradox by characterizing the interaction between stat92e and hp1 ; they manipulated the expression levels of both proteins and assessed the effects on pev . they found that the enhanced heterochromatic gene silencing obtained with increased levels of stat92e , was countered by lowering hp1 levels , while the reduction in silencing seen with lower hp1 levels was countered by increasing stat92e levels . thus , these data show that stat92e and hp1 function interdependently to effect heterochromatic gene silencing . shi et al . then assessed more directly how manipulating stat92e levels affects heterochromatin in larvae and embryos . they generated larvae with clones of cells having different levels of stat92e , and detected heterochromatin by immunostaining with antibodies directed against h3mk9 or hp1 . clonal overexpression of stat92e resulted in higher levels of h3mk9 and hp1 staining in comparison with neighboring wild - type cells , corroborating the results of the pev assays . on the other hand , clones of larval cells with a loss - of - function mutant stat92e , showed a clear reduction in hp1 foci ; moreover , in drosophila embryos with lower levels of stat92e , localization of hp1 to centromeric heterochromatin was disrupted , and there was less h3mk9 protein . thus , all of these data support the idea that stat92e plays an important role in hp1 localization in heterochromatin . indeed , the immunostaining of larval cells showed stat92e to be localized mainly in the nucleus , much of it co - localized with hp1 . the role of stat92e in hp1 localization was confirmed by chromatin immunoprecipitation assays with an anti - hp1 antibody , using cultured drosophila s2 cells . immunoprecipitations were done before and after treatment of the cells with rnai directed against stat92e . the 1360 transposable element served as a heterochromatin marker , because this repetitive sequence is found in constitutively heterochromatic regions of all drosophila chromosomes ; and chromatin immunoprecipitation has demonstrated that hp1 binding to these sequences is enriched . the association of hp1 with the 1360 element was indeed significantly reduced after rnai knockdown of stat92e . co - immunoprecipitation studies then demonstrated that stat92e and hp1 associate physically ; and this interaction was abolished when both hp1-binding motifs of stat92e were mutated . when immunoprecipitations were done in hop/+ embryos , less hp1 was co - immunoprecipitated with stat92e than in wild - type embryos . thus , in a situation where there was less phosphorylated stat92e relative to unphosphorylated stat92e , more stat92e was found associated with hp1 . taken together , these findings raised the possibility that it is the unphosphorylated form of stat92e that interacts with hp1 . if this hypothesis were in fact correct , the paradox that both more jak activity and less stat92e leads to heterochromatin disruption could be resolved , since more jak activity leads to more phosphorylated , but less unphosphorylated stat92e . when immunostaining was done with an anti - phospho - stat92e antibody , phosphorylated stat92e did not co - localize with hp1 , supporting the idea that it is the unphosphorylated form of stat92e that co - localizes with hp1 . to study how phosphorylation of stat92e might destabilize heterochromatin , an ex vivo assay was performed in which cultured salivary glands , carrying a stat92e - gfp transgene , were treated with the tyrosine phosphatase inhibitor pervanadate to increase stat92e phosphorylation , and stat92e and hp1 localization were studied . before pervanadate treatment , stat92e was found in both the cytoplasm and the nucleus , and the nuclear portion was mostly co - localized with hp1 . after 20 min of pervanadate treatment , an enrichment of nuclear stat92e - gfp was observed , but it was no longer co - localized with hp1 . after 60 min of pervanadate treatment , hp1 was also dispersed from heterochromatin . if , however , the salivary glands expressed an unphosphorylatable stat92e - gfp mutant transgene rather than wild - type stat92e - gfp , the mutant stat92e remained co - localized with hp1 upon pervanadate treatment . therefore , these data strongly support the idea that phosphorylation of stat92e causes it to dissociate from heterochromatin , followed by displacement of hp1 . the dissociation of phosphorylated stat92e from heterochromatin was corroborated by chromatin immunoprecipitation experiments with an anti - stat92e antibody that showed an enrichment of 1360 sequences in stat92e  chromatin complexes before , but not after , pervanadate treatment . inhibition of protein synthesis by cycloheximide treatment did not prevent the hp1 dispersal induced by pervanadate ; heterochromatin loss was actually accelerated in the presence of cycloheximide . these findings suggest that new protein synthesis is not required for the disruption of heterochromatin seen upon stat92e phosphorylation , and hence imply that heterochromatin destabilization is not dependent upon induction of stat92e transcriptional targets via the canonical jak - stat pathway . have characterized a new , non - canonical mode of jak - stat regulation . in this non - canonical mode , work with mammalian cells has yielded results that are concordant with the findings of shi et al . nuclear jak2 has been detected in hematopoietic cells , oocytes , and perhaps other cell types . in hematopoietic cells , jak2 has been shown to sp.ecifically phosphorylate histone h3 at amino acid y41 , decreasing its association with hp1 ; therefore , in this case , jak2 activity disrupts heterochromatin by phosphorylation of histone h3 . unphosphorylated stat1 , stat3 , and low levels of stat5a have also been found in the nuclei of mammalian cells . recently , the tumor suppressor function of unphosphorylated stat has been extended to a mammalian system . have shown that increased levels of unphosphorylated stat suppress tumor formation in a xenogeneic mouse model of human colon cancer . a loss of genome stability can result in cell death , premature aging , or cancer . do jak and stat , then , have a role in preserving genome stability by virtue of their regulation of heterochromatin ? yan et al . addressed this question by genetically manipulating levels of stat92e and hp1 in drosophila , and determining how resistant the animals were to radiation - induced dna damage . upon receiving low levels of ionizing radiation , drosophila larval cells respond by cell cycle arrest , which results in a dramatic reduction in the number of mitotic cells . cells in mitosis can be readily identified and enumerated by immunostaining of larval imaginal discs , groups of tissue - specific progenitor cells , with antibodies directed against the mitotic marker phosphohistone h3 . in control animals , with wild - type levels of stat92e , yan et al . found the number of mitotic cells in wing imaginal discs to be reduced nearly 10-fold after exposure to low dose -irradiation , when compared with non - irradiated discs . when levels of stat92e were decreased , the number of mitotic cells after irradiation decreased even further , by an average of 3-fold when compared with control larvae . conversely , an increase in the levels of unphosphorylated stat92e resulted in a 2-fold increase in mitotic cells compared with controls . these findings are consistent with the idea that the increased levels of heterochromatin seen with higher levels of unphosphorylated stat92e , impart greater genomic stability and resistance to dna damage . if this idea is correct , then lowering the levels of hp1 should result in a greater sensitivity to radiation . found that larvae with reduced levels of hp1 did indeed exhibit fewer mitotic cells in their wing discs , indicating a greater sensitivity to radiation . how do changes in heterochromatin levels affect the response to radiation ? does a decrease in heterochromatin levels result in more dna damage , or is the response to dna damaging agents impaired ? to answer this question , yan et al . examined dna damage in a more direct fashion by assessing the levels of drosophila phosphorylated h2av , the equivalent of the mammalian phosphorylated histone variant h2ax ( -h2ax ) , which serves as a marker for dna damage . initial experiments were performed with larval brains from non - irradiated animals having reduced levels of either stat or hp1 , or carrying the hop mutation . immunostaining with anti--h2ax antibodies revealed higher levels of h2av in these animals than in wild type . thus , loss of heterochromatin is associated with more dna damage even in non - irradiated animals . as expected , increasing the levels of heterochromatin , by overexpressing hp1 or an unphosphorylatable stat92e mutant , suppressed the increase in h2av associated with hop . yan et al . then used immunostaining with anti--h2ax antibodies to assess the effect of increased heterochromatin levels on radiation - induced dna damage . these experiments utilized larvae expressing unphosphorylatable stat92e in the posterior but not the anterior compartment of their wing imaginal discs . after low dose irradiation of the larvae , the wing discs were immunostained , and the numbers of h2av foci in the posterior and anterior compartments were compared . the posterior compartment indeed showed significantly fewer h2av foci , lending further support to the idea that unphosphorylated stat92e and heterochromatin protect the genome from dna damage . to distinguish between effects on dna damage and on dna repair , yan et al . embryos that were either wild type or with reduced levels of heterochromatin were collected , and total protein was extracted and subjected to western blotting with anti--h2ax antibodies . in both mutant and wild - type embryos , levels of h2av were increased at ten minutes after irradiation ( though to different degrees ) , and then gradually decreased to basal levels by 24 h after irradiation , suggesting that all of the animals had a similar ability to repair dna damage . thus , decreased levels of heterochromatin result in more -radiation induced dna damage , but do not seem to impair the dna repair process . how might reduced levels of heterochromatin lead to greater dna damage ? since it is known that loss - of - function hp1 mutants show defects in chromosome compaction , yan et al . considered the possibility that lower heterochromatin levels were leading to improper dna compaction , which in turn was leading to chromosomal breakage . they therefore investigated how reductions in stat92e or hp1 might affect dna compaction , by examining metaphase chromosomes in the large diploid nuclei of larval brain neuroblasts . they found that larvae with lower levels of stat92e or hp1 exhibited significantly longer mitotic chromosomes than wild - type larvae , suggesting that the chromosomes were indeed improperly condensed . they also examined mitotic nuclei in early embryonic syncytia , where others have shown that a reduction in maternally supplied hp1 results in chromosomal condensation and segregation defects . in embryos lacking maternally supplied stat92e , and also in hop embryos , yan et al . found that a substantial number of the metaphase chromosomes were improperly condensed and frequently exhibited chromosome bridges , phenomena seen only very rarely in wild - type embryos . they showed that irradiation during drosophila larval growth resulted in missing or shortened macrochaetes , the large bristles found on the thorax of adult flies . when levels of heterochromatin were reduced , significantly more flies showed bristle loss than did wild - type flies . with increased levels of heterochromatin , fewer flies exhibited bristle loss . without irradiation , neither wild - type nor mutant flies showed bristle loss . to determine whether bristle loss was indeed correlated with chromosome breakage , yan et al . did pulsed - field gel electrophoresis of genomic dna from irradiated larvae . in animals with reduced levels of heterochromatin , the gel revealed more broken dna , visualized as faster - migrating dna fragments , than in wild - type animals . thus , these results support the idea that lower levels of heterochromatin make flies more susceptible to radiation - induced chromosome breaks . higher doses of -radiation can cause lethality in drosophila . do higher levels of heterochromatin afford protection against such lethality ? to answer this question , larvae with different levels of heterochromatin were exposed to a high dose of -radiation , and the percentage of larvae giving rise to adult flies was determined . animals with increased hp1 levels showed a 3-fold increase in viability compared with wild type , while animals with reduced heterochromatin levels showed greater lethality than wild type . these results , then , are consistent with the idea that reduced heterochromatin levels lead to improper chromosomal condensation during mitosis and to dna breakage , thereby increasing tissue sensitivity to radiation . when genome stability is enhanced by higher levels of heterochromatin , however , a dramatic increase in the survival of irradiated animals ensues . do higher levels of heterochromatin only prolong the lifespan of irradiated animals , or does this salutary effect apply more generally ? larson et al . addressed this issue by genetically manipulating levels of hp1 , jak , and stat in drosophila , and determining the effects on lifespan . a moderate increase in hp1 levels significantly extended lifespan . on the other hand , lifespan was also shortened when levels of stat92e were reduced , or when jak was overexpressed . do aged flies , then , have reduced levels of heterochromatin ? to answer this question , larson et al . using immunostaining to examine hp1 foci in enterocyte nuclei , where pericentric heterochromatin is readily discernible at the chromocenter . old flies , however , showed a dramatic reduction in heterochromatin , with many enterocyte nuclei lacking distinct hp1 foci . to confirm that less hp1 is localized to heterochromatin in old flies than young ones , chromatin immunoprecipitation was done with an anti - hp1 antibody ; the amount of immunoprecipitated transposable element 1360 , a representative heterochromatic sequence , was then determined by polymerase chain reaction . in young wild - type flies , hp1 was indeed associated with 1360 , but not in old wild - type flies . thus , these data support the concept that heterochromatin levels drop with age . in flies with higher hp1 levels , due to hp1 expression from a transgene , however , hp1 and 1360 were associated in old flies as well as young ones . does heterochromatin loss in aged flies result in the de - repression of silent genes ? when larson et al . looked at expression of a heterochromatinized transgene , they found it to be silent in young flies but expressed in old flies , suggesting that lower heterochromatin levels do cause de - repression of silenced genes . if de - repression of silenced genes occurs during aging , which genes might be critical to the aging process ? approached this issue by seeking more information , on the organismal level , about how fruit flies age . might there be similarities to aging in mammals ? to monitor changes in fly behavior over time , video recordings were done . the recordings revealed that aged flies exhibit a gradual loss of mobility , eventually becoming immobile . fly mobility was quantified by measuring the speed with which flies moved from the bottom of a vial in which they were confined , toward the top . when flies with different levels of heterochromatin were compared , the flies with reduced heterochromatin levels lost mobility significantly faster than wild - type flies , while those with increased heterochromatin levels were mobile for a longer time . thus , these results suggest a possible association between heterochromatin loss and muscle degeneration in old flies . to assess muscle integrity , larson et al . looked at the large intestinal wall muscles of drosophila , which can be readily visualized in adult flies following minimal dissection . whole - mount staining with fluorescinated phalloidin was used to assess the integrity of these muscles in young and old flies . in wild - type flies , progressive muscle degeneration was seen with aging ; muscle fiber breakage was first detected at 20 d after eclosion , and extensive breakage was seen at 40 d. when heterochromatin levels were reduced , extensive muscle breakage was apparent at 20 d , whereas with increased heterochromatin levels , muscle integrity was preserved beyond 40 d. furthermore , muscle integrity was found to correlate well with fly mobility . thus , maintenance of heterochromatin levels is indeed important for maintaining muscle structure , fly mobility , and viability . what critical genes might be affected by heterochromatin loss ? in drosophila , fragmentation of the nucleolus , the site of rrna synthesis , has been shown to occur when heterochromatin levels are lowered by a decrease in hp1 or h3mk9 . , looked at larvae with lower heterochromatin levels resulting from jak overactivation or a loss of stat92e , they also detected nucleolar fragmentation . on the other hand , hp1 overexpression suppressed the nucleolar fragmentation associated with jak overexpression . nucleolar fragmentation has been attributed to genomic instability at the rdna locus , presumably from the illegitimate recombination of these highly repetitive sequences . larson et al . examined illegitimate rdna recombination by measuring levels of extrachromosomal circular dna ( ecc ) , and indeed found increased ecc in animals with decreased heterochromatin levels . intriguingly , instability at the rdna locus in yeast also results in increased ecc , and has been demonstrated to accelerate aging in that organism . . found that heterochromatin loss resulted in increased transcription from the rdna locus , whereas moderate hp1 overexpression , at levels shown to extend lifespan , resulted in a significant decrease in transcription . flies with reduced heterochromatin also had greater body weight than wild - type flies , while flies moderately overexpressing hp1 had significantly lower body weight . body weight is an indication of growth rate , a higher growth rate often being associated with a shorter lifespan . the inverse correlation of heterochromatin levels with body weight therefore suggests that heterochromatin regulation of the rdna locus may be important for viability in drosophila . thus , larson et al . have identified two means by which maintenance of heterochromatin levels may have a salutary effect on lifespan in drosophila . the work discussed here demonstrates that jak and stat perform many non - canonical functions in the cell . activated jak causes disruption of heterochromatin , while unphosphorylated stat stabilizes heterochromatin and acts as a tumor suppressor . the higher levels of heterochromatin due to increased levels of stat , or hp1 , extend lifespan . moreover , higher heterochromatin levels confer greater resistance to radiation - induced dna damage , by maintaining genomic stability . lower heterochromatin levels , on the other hand , result in a shorter lifespan and greater sensitivity to radiation - induced dna damage . the tumor suppressive function of unphosphorylated stat has recently been demonstrated in mammalian cells as well ( fig . role of stat in heterochromatin and in genome stability . in the non - canonical jak - stat pathway in drosophila , unphosphorylated stat stabilizes heterochromatin , while jak activation increases stat phosphorylation and causes heterochromatin disruption . higher levels of heterochromatin confer greater resistance to radiation - induced dna damage , and are important for maintaining genomic stability . in addition , heterochromatin formation may lead to the silencing of genes that promote tumorigenesis or aging . the regulation of heterochromatin by jak and stat92e indicates that these molecules have a more global role in the regulation of nuclear processes than was previously appreciated . interestingly , it has recently been reported that another transcription factor , atf-2 , which is activated by stress - induced kinases , behaves in a similar fashion to stat . drosophila atf-2 ( datf-2 ) , apparently in its unphosphorylated form , is involved in heterochromatin assembly ; when datf-2 is phosphorylated , heterochromatin is disrupted . do other signaling pathways and other transcription factors also regulate heterochromatin in a more global fashion ? how is this regulation of heterochromatin coordinated with the other processes occurring in the cell nucleus ? mammalian stats , particularly stat3 , appear to perform a number of non - canonical functions in the cytoplasm . does drosophila stat also perform non - canonical functions in the cytoplasm ? what is the significance of these non - canonical nuclear and cytoplasmic functions of jak and stat ? one possibility is that stats , and to a lesser extent jaks , have evolved to play many different but unrelated roles in the cell . another possibility is the existence of a novel level of nuclear and cytoplasmic organization , in which jak and stat have important roles . should the latter possibility be substantiated , it might lead to significant , new insights into cellular function .
the canonical jak - stat signaling pathway transmits signals from the cell membrane to the nucleus , to regulate transcription of particular genes involved in development and many other physiological processes . 
 it has been shown in drosophila that jak and stat also function in a non - canonical mode , to regulate heterochromatin . 
 this review discusses the non - canonical functioning of jak and stat , and its effects on biological processes . decreased levels of activated jak and increased levels of unphosphorylated 
 stat generate higher levels of heterochromatin . 
 these higher heterochromatin levels result in suppression of hematopoietic tumor - like masses , increased resistance to dna damage , and longer lifespan .