JMJD3 aids in reprogramming of bone marrow progenitor cells to hepatic phenotype through epigenetic activation of hepatic transcription factors

Abstract

The strictly regulated unidirectional differentiation program in some somatic stem/progenitor cells has been found to be modified in the ectopic site (tissue) undergoing regeneration. In these cases, the lineage barrier is crossed by either heterotypic cell fusion or direct differentiation. Though studies have shown the role of coordinated genetic and epigenetic mechanisms in cellular development and differentiation, how the lineage fate of adult bone marrow progenitor cells (BMPCs) is reprogrammed during liver regeneration and whether this lineage switch is stably maintained are not clearly understood. In the present study, we wanted to decipher genetic and epigenetic mechanisms that involve in lineage reprogramming of BMPCs into hepatocyte-like cells. Here we report dynamic transcriptional change during cellular reprogramming of BMPCs to hepatocytes and dissect the epigenetic switch mechanism of BM cell-mediated liver regeneration after acute injury. Genome-wide gene expression analysis in BM-derived hepatocytes, isolated after 1 month and 5 months of transplantation, showed induction of hepatic transcriptional program and diminishing of donor signatures over the time. The transcriptional reprogramming of BM-derived cells was found to be the result of enrichment of activating marks (H3K4me3 and H3K9Ac) and loss of repressive marks (H3K27me3 and H3K9me3) at the promoters of hepatic transcription factors (HTFs). Further analyses showed that BMPCs possess bivalent histone marks (H3K4me3 and H3K27me3) at the promoters of crucial HTFs. H3K27 methylation dynamics at the HTFs was antagonistically regulated by EZH2 and JMJD3. Preliminary evidence suggests a role of JMJD3 in removal of H3K27me3 mark from promoters of HTFs, thus activating epigenetically poised hepatic genes in BMPCs prior to partial nuclear reprogramming. The importance of JMJD3 in reprogramming of BMPCs to hepatic phenotype was confirmed by inhibiting catalytic function of the enzyme using small molecule GSK-J4. Our results propose a potential role of JMJD3 in lineage conversion of BM cells into hepatic lineage.

Potential application of cell reprogramming techniques for cancer research

“…JMJD3 has been reported as an epigenetic enhancer of lineage conversion from bone marrow progenitors to liver cells [204]. Agathocleous et al [205] and Cimmino et al [206] reported that vitamin C regulated HSCs and suppressed leukemogenesis by modulating TET2 activity.…”

“…Chromatin modifiers, such as the EZH2 and ASCL1 components, are also useful for DR to iNSCs or motor neurons [ 183 , 201 – 203 ]. JMJD3 has been reported as an epigenetic enhancer of lineage conversion from bone marrow progenitors to liver cells [ 204 ]. Agathocleous et al [ 205 ] and Cimmino et al [ 206 ] reported that vitamin C regulated HSCs and suppressed leukemogenesis by modulating TET2 activity.…”

Epigenetic Modifications of the Liver Tumor Cell Line HepG2 Increase Their Drug Metabolic Capacity

“…The hepatic key regulator HNF4α showed only minimal levels of H3K27me3 enrichment at these promoters in primary hepatocytes. In other cells, removal of H3K27me3 from the HNF4α promoter resulted in transcriptional activation and expression of liver enrichment transcription factors [26]. A degradation of this methylation in HepG2 could be associated with an increased expression of HNF4α which can be attributed to the activity of KDM6B [25].…”

Targeting Epigenetic Aberrations in Pancreatic Cancer, a New Path to Improve Patient Outcomes?

“…The use of drugs to rewrite a chromatin landscape is a concept that is already in play in various fields centered around epigenetics. Much of the current research in stem cell therapy and regenerative medicine makes use of epigenetic drugs to manipulate cells and elicit a desired phenotype [ 33 , 34 ]. These fields have experienced tremendous success and more importantly, have shed light on the potential to translate these concepts into PDAC research.…”