Figure 4.

The indirect epigenetic pathway. An epigenetic factor operating through an indirect pathway interferes with transcriptional machinery. Chronic exposure to an epigenetic factor can lead to the retention of an already altered state of transcriptional machinery. The transcriptional machinery (bound or unbound to the gene regulatory regions i.e., promoters/enhancers) includes a number of proteins like transcription factors, activators and co-activators, repressors and co-repressors and nucleosome or chromatin remodeling complexes. For simplicity, these proteins are Fectively termed as “Gene regulatory protein” for this figure. (A) A gene regulatory protein might affect the status of RNA Polymerase (1) By inhibiting it from binding to a transcriptional apparatus or forming one or (2) by facilitating the binding of RNA Polymerase as well as formation of a transcriptional apparatus essential for the initiation of transcription. (B) A gene regulatory protein might also affect the status of epigenetic enzymes like DNMTs, HDACs, HATs, HMTs, HDMs, etc., which are responsible for the addition or removal of epigenetic tags (methyl group on DNA or histone, acetyl group on histones) on gene regulatory regions. This can be (1) By inhibiting epigenetic enzymes from binding to the gene regulatory regions and hence prohibiting the addition or removal of epigenetic tags (2) By facilitating the binding of epigenetic enzymes to gene regulatory regions and hence allowing the addition or removal of epigenetic tags. Such retention of a gene regulatory protein due to chronic exposure to an epigenetic factor might result in a permanent change in the epigenetic profile and/or gene expression of a specific gene affected by that epigenetic factor through an indirect pathway.