Activation of Inactive Hepatocytes through Histone Acetylation

Abstract

The mechanisms by which hepatic function is maintained after extensive parenchymal loss are unclear. In this study, we propose a novel concept of "functional heterogeneity" of hepatocytes based on their different expression of acetylated histones, the markers of active gene transcription, to explain the powerful compensatory capability of the liver. In the healthy human liver, only a fraction of the hepatocytes were marked by acetylated histones (ac-H2AK5, ac-H2BK5, ac-H3K9, ac-H3K14, ac-H3K27, and ac-H3K9/14). With the progression of cirrhosis, the ratio of the positive cells was gradually elevated, accompanied by the gradual exhaustion of the negative cells. By examining the global transcriptome of the mouse hepatocytes, we observed that the primed genes in the positive cells were much more numerous than those in negative cells. In a 70% hepatectomized mouse, the remnant hepatocytes were extensively activated, and the liver function was well maintained even when regeneration was severely inhibited. The functional compensation was absolutely dependent on the elevated expression of acetyl-histones. Additionally, when liver regeneration was blocked, the metabolism-related genes seemed to be preferentially transcribed. In conclusion, we demonstrate that normally, part of the active hepatocytes are competent for routine physiological requirements. The inactive hepatocytes, delicately regulated by acetyl-histones, act as a functional reservoir for future activation to restore the liver func- The liver has a unique regenerative capacity that restores its mass and function after diverse injuries, including a 70% to 95% partial hepatectomy (PH) in rodents and humans, by the proliferation of differentiated hepatocytes.1-3 Liver regeneration is commonly considered to be the adaptive process by which liver structure and function are recovered. However, in some cases, rodents can survive for an extended period of time after a 70% PH even when liver regeneration is chemically disrupted. 4 -6 Similarly, despite the on-going decrement of hepatocytes, patients suffering from chronic cirrhosis can keep their liver function normal for many years. [7][8][9] This evidence suggests that the remnant liver can compensate for the initial loss of hepatic function independent of cell mass recovery. The powerful compensatory capability of the liver raises an interesting question: why does the body need so many hepatocytes when a minority of the liver mass seems competent? We hypothesize that only a subset of hepatocytes is functionally active at any given time, or each individual hepatocyte is only partially active. The subset of the inactive or the incompletely activated hepatocytes, therefore, acts as a functional reservoir that can be invoked for functional compensation. Molecular

PharmGKB summary

“…This is supported by slow acetylator mouse models in which todralazine treatment did not induce liver failure on its own, however in mice with anti-CD95 induced liver injury, resulted in mortality, smaller livers and impaired histone acetylation compared to controls despite similar alanine transaminase (ALT) levels [65]. The role of HATs, their cofactors, and histone acetylation in liver regeneration after toxic injury has been shown in other studies [138, 139]. This may be another contributing factor to drug-induced liver injury that affects association with NAT2 genotype.…”

X Chromosome Crossover Formation and Genome Stability inCaenorhabditis elegansAre Independently Regulated byxnd-1

“…These data intimate that H2AK5ac hinders DSB formation. The function of this histone modification is largely unknown, but several reports implicate this mark in transcriptional activation (Shi et al 2011; Rajagopal et al 2014). One possibility is that H2AK5ac normally localizes to the active genes, which are found in preponderance in the central gene clusters on C. elegans autosomes (Barnes et al 1995), facilitating their transcription but inhibiting COs.…”

Genome-wide enhancer prediction from epigenetic signatures using genetic algorithm-optimized support vector machines

“…These unique methylation patterns at enhancers include the activating marks H3K4Me1 and H3K4Me3 ( 25 ), and a transcriptional silencing flag (H3R2Me2) ( 52 ). The enhancers also contain an acetylation mark (H2BK5Ac) that strongly correlates to gene expression profiles ( 53 ). The five epigenetic mark rule was implemented as a penalty function rather than as a priori cut-off: the models are actually allowed to combine more than five epigenetic marks as long as every extra mark is associated with an increase of at least 0.1 units in the AUC so that any five-mark model is substantially out-performed by a six (or more) mark model.…”