The transposon-driven evolutionary origin and basis of histone deacetylase functions and limitations in disease prevention

Abstract

Histone deacetylases (HDACs) are homologous to prokaryotic enzymes that removed acetyl groups from non-histone proteins before the evolution of eukaryotic histones. Enzymes inherited from prokaryotes or from a common ancestor were adapted for histone deacetylation, while useful deacetylation of non-histone proteins was selectively retained. Histone deacetylation served to prevent transcriptions with pathological consequences, including the expression of viral DNA and the deletion or dysregulation of vital genes by random transposon insertions. Viruses are believed to have evolved from transposons, with transposons providing the earliest impetus of HDAC evolution. Because of the wide range of genes potentially affected by transposon insertions, the range of diseases that can be prevented by HDACs is vast and inclusive. Repressive chromatin modifications that may prevent transcription also include methylation of selective lysine residues of histones H3 and H4 and the methylation of selective DNA cytosines following specific histone lysine methylation. Methylation and acetylation of individual histone residues are mutually exclusive. While transposons were sources of disease to be prevented by HDAC evolution, they were also the source of numerous and valuable coding and regulatory sequences recruited by “molecular domestication.” Those sequences contribute to evolved complex transcription regulation in which components with contradictory effects, such as HDACs and HATs, may be coordinated and complementary. Within complex transcription regulation, however, HDACs remain ineffective as defense against some critical infectious and non-infectious diseases because evolutionary compromises have rendered their activity transient.

DNMT1 modulation in chronic hepatitis B patients and hypothetic influence on mitochondrial DNA methylation status during long‐term nucleo(t)side analogs therapy

“…Among these, there are increasing indication that certain chemicals substances and drugs may regulate gene expression not only during but also after exposure . Epigenetic modification of the mitochondrial genome has been widely debated, but the most recently published data highlight how the methylation of cytosines in the mitochondrial DNA is likely to be much more frequent than previously believed .…”