Abstract
The dynamic nature of the chromatin epigenetic landscape plays a key role in the establishment and maintenance of cell identity, yet the factors that affect the dynamics of the epigenome are not fully known. Here we find that the ubiquitous nucleosome binding proteins HMGN1 and HMGN2 preferentially colocalize with epigenetic marks of active chromatin, and with cell-type specific enhancers. Loss of HMGNs enhances the rate of OSKM induced reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs), and the ASCL1 induced conversion of fibroblast into neurons. During transcription factor induced reprogramming to pluripotency, loss of HMGNs accelerates the erasure of the MEF-specific epigenetic landscape and the establishment of an iPSCs-specific chromatin landscape, without affecting the pluripotency potential and the differentiation potential of the reprogrammed cells. Thus, HMGN proteins modulate the plasticity of the chromatin epigenetic landscape thereby stabilizing, rather than determining cell identity.
Highlights
The dynamic nature of the chromatin epigenetic landscape plays a key role in the establishment and maintenance of cell identity, yet the factors that affect the dynamics of the epigenome are not fully known
We study the conversion of wild type and Hmgn1−/− / Hmgn2−/− (DKO) mouse embryonic fibroblasts (MEFs), which lack both HMGN1 and HMGN2, into pluripotent cells following the ectopic expression of Oct[4], Sox[2], Klf[4], and c-Myc (OSKM)
Comparison of the genome wide organization of high mobility group N (HMGN) with data generated in our laboratory and with data available in Encode[6,25], indicates that in all the three cell types, HMGNs colocalize with epigenetic marks of active chromatin such as H3K4me[3], H3K27ac and H3K4me[1], and with DNase I or Assay of Transposase Accessible Chromatin (ATAC) sensitive sites, that mark chromatin regions which are relatively de-condensed and preferentially accessible to regulatory factors
Summary
The dynamic nature of the chromatin epigenetic landscape plays a key role in the establishment and maintenance of cell identity, yet the factors that affect the dynamics of the epigenome are not fully known. Additional global regulators of chromatin organization, such as the chromatin binding High Mobility Group (HMG) architectural proteins[15], could play a role in safeguarding cell identity[16,17], this possibility has not yet been fully explored Chromatin architectural proteins such as H1 and HMGs are ubiquitously expressed in the nuclei of all vertebrate cells potentially affecting epigenetic processes and the maintenance of cell identity in many cell types. We analyze the genome-wide organization of HMGNs in the chromatin of several cells types and find that these proteins colocalize with epigenetic marks of active chromatin and with cell-specific regulatory sites, raising the possibility that they play a role in cell fate decisions To test this possibility, we study the conversion of wild type and Hmgn1−/− / Hmgn2−/− (DKO) MEFs, which lack both HMGN1 and HMGN2, into pluripotent cells following the ectopic expression of Oct[4], Sox[2], Klf[4], and c-Myc (OSKM). Our studies reveal an essential role for the ubiquitous HMGN proteins in regulating chromatin dynamics during reprogramming, and indicate that their presence at cell-type specific regulatory sites stabilizes the cellular epigenetic landscape that maintains cell identity
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