Reversibility and heritability of liver fibrosis:Implications for research and therapy

Liver fibrosis continues to be a major health problem worldwide due to lack of effective therapy.If the etiology cannot be eliminated,liver fibrosis progresses to cirrhosis and eventually to liver failure or malignancy;both are associated with a fatal outcome.Liver transplantation,the only curative therapy,is still mostly unavailable.Liver fibrosis was shown to be a reversible process;however,complete reversibility remains debatable.Recently,the molecular markers of liver fibrosis were shown to be transmitted across generations.Epigenetic mechanisms including DNA methylation,histone posttranslational modifications and noncoding RNA have emerged as major determinants of gene expression during liver fibrogenesis and carcinogenesis.Furthermore,epigenetic mechanisms have been shown to be transmitted through mitosis and meiosis to daughter cells and subsequent generations.However,the exact epigenetic regulation of complete liver fibrosis resolution and inheritance has not been fully elucidated.This communication will highlight the recent advances in the search for delineating the mechanisms governing resolution of liver fibrosis and the potential for multigenerational and transgenerational transmission of fibrosis markers.The fact that epigenetic changes,unlike genetic mutations,are reversible and can be modulated pharmacologically underscores the unique opportunity to develop effective therapy to completely reverse liver fibrosis,to prevent the development of malignancy and to regulate heritability of fibrosis phenotype.

Epigenetic Tumor Response to Hypoxia: An Epimutation Pattern and a Method of Multi Targeted Epigenetic Therapy (MTET)

In most cases, cancer develops as a result of non-inheritable somatic mutations (epimutations), acquired by the individual adult cell, during the evolution of the cell, and propagated into an expanding clone of progeny of the cells by natural selection [1]. The role of microenvironment in selection for such acquired mutations, or epimutations, is a focus of scientific research in carcinogenesis [2]. Here we describe a defective DNA response to hypoxia due to epigenetic aberrancies, in cancer cellular biology [3]. We also summarize a literature review on hypoxia mediated epigenetic responses, and its role in carcinogenesis and metastasis. Further, we review a novel method of treating hypoxic solid tumors with a combination of epigenetic modifiers with both in vitro and in vivo results in human, translating to an improved prognosis and clinical outcome. We propose that this approach both independently and synergistically (with the current standard of care) can provide an improved outcome.

Epigenetic reduction of DNA repair in progression to gastrointestinal cancer

Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal(GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations(i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy.

Charting epimutation dynamics in human hematopoietic differentiation Xiaohuan Qina

DNA methylation plays a critical role in hematopoietic differentiation.Epimutation is a stochastic variation in DNA methylation that induces epigenetic heterogeneity.However,the effects of epimutations on normal hematopoiesis and hematopoietic diseases remain unclear.In this study,we developed a Julia package called EpiMut that enabled rapid and accurate quantification of epimutations.EpiMut was used to evaluate and provide an epimutation landscape in steady-state hematopoietic differentiation involving 13 types of blood cells ranging from hematopoietic stem/progenitor cells to mature cells.We showed that substantial genomic regions exhibited epigenetic variations rather than significant differences in DNA methylation levels between the myeloid and lymphoid lineages.Stepwise dynamics of epimutations were observed during the differentiation of each lineage.Importantly,we found that epimutation significantly enriched signals associated with lineage differentiation.Furthermore,epimutations in hematopoietic stem cells(HSCs)derived from various sources and acute myeloid leukemia were related to the function of HSCs and malignant cell disorders.Taken together,our study comprehensively documented an epimutation map and uncovered its important roles in human hematopoiesis,thereby offering insights into hematopoietic regulation.