text: Trans-regulatory elements work through an intermolecular interaction between two different molecules and so are said to be "acting in trans". For example (1) a transcribed and translated transcription factor protein derived from the trans-regulatory element; and a (2) DNA regulatory element that is adjacent to the regulated gene. This is in contrast to cis-regulatory elements that work through an intramolecular interaction between different parts of the same molecule: (1) a gene; and (2) an adjacent regulatory element for that gene in the same DNA molecule. Additionally, each trans-regulatory element affects a large number of genes on both alleles, while cis-regulatory element is allele specific  and only controls genes nearby.
  Exonic and promoter sequences of the genes are significantly more conserved than the genes in cis- and trans- regulatory elements. Hence, they have higher resistance to genetic divergence, yet retains its susceptibility to mutations in upstream regulators. This accentuates the significance of genetic divergence within species due to cis- and trans-regulatory variants. 
  Trans- and cis-regulatory elements co-evolved rapidly in large-scale to maintain gene expression. They often act in opposite directions, one up-regulates while another down-regulates, to compensate for their effects on the exonic and promoter sequences they act on. Other evolutionary models, such as the independent evolution of trans- or cis-regulatory elements, were deemed incompatible in regulatory systems. Co-evolution of the two regulatory elements was suggested to arise from the same lineage.
  TRE is more evolutionary constraint than cis-regulatory element, suggesting a hypothesis that TRE mutations are corrected by CRE mutations to maintain stability in gene expression. This makes biological sense, due to TREs effect on a broad range of genes and CREs compensatory effect on specific genes. Following a TRE mutation, accumulation of CRE mutations act to fine-tune the mutative effect.