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Compartmentalization of HP1 Proteins in Pluripotency Acquisition and Maintenance.

ABSTRACT: The heterochromatin protein 1 (HP1) family is involved in various functions with maintenance of chromatin structure. During murine somatic cell reprogramming, we find that early depletion of HP1γ reduces the generation of induced pluripotent stem cells, while late depletion enhances the process, with a concomitant change from a centromeric to nucleoplasmic localization and elongation-associated histone H3.3 enrichment. Depletion of heterochromatin anchoring protein SENP7 increased reprogramming efficiency to a similar extent as HP1γ, indicating the importance of HP1γ release from chromatin for pluripotency acquisition. HP1γ interacted with OCT4 and DPPA4 in HP1α and HP1β knockouts and in H3K9 methylation depleted H3K9M embryonic stem cell (ESC) lines. HP1α and HP1γ complexes in ESCs differed in association with histones, the histone chaperone CAF1 complex, and specific components of chromatin-modifying complexes such as DPY30, implying distinct functional contributions. Taken together, our results reveal the complex contribution of the HP1 proteins to pluripotency.

SUBMITTER: Zaidan NZ

PROVIDER: S-EPMC5830946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Compartmentalization of HP1 proteins in pluripotency acquisition and maintenance

Project description:Embryonic stem cells (ESCs) have a hyperdynamic chromatin structure characterized by fewer discrete foci of heterochromatin protein 1 family of proteins (HP1) compared to somatic cells. During reprogramming of somatic cells, depletion of HP1γ early, reduced, while depletion later, enhanced the generation of induced pluripotent stem cells (iPSCs); concomitant with a change from a centromeric to nucleoplasmic localization. To identify the interactome of HP1γ in different biochemical environment in ESCs, we compared protein complexes of HP1γ at 0.42M salt (Dignam et al, 1983), with micrococcal nuclease (MCN) digestion with 0.3M NaCl, and MCN with 0.5M NaCl. To understand the effectors of the change in localization, we isolated protein complexes containing HP1γ in ESCs and compared the profile to that in partially reprogrammed intermediates called pre-iPSCs. Given the differential distribution of the HP1 family in ESCs, we also compared the protein interactome of HP1γ in ESCs with that of HP1α and HP1β. In addition, we probed histone associations of HP1γ in ESCs further by querying the histone post-translational modifications that were detectable. The HP1 proteins themselves are decorated with multiple PTMs, several of which we have found to be novel. Taken together our results reveal the complex contribution of the HP1 proteins to pluripotency.

2017-12-13 | PXD006817 | Pride

The role of ?-ketoglutarate-dependent proteins in pluripotency acquisition and maintenance.

Project description:?-Ketoglutarate is an important metabolic intermediate that acts as a cofactor for several chromatin-modifying enzymes, including histone demethylases and the Tet family of enzymes that are involved in DNA demethylation. In this review, we focus on the function and genomic localization of these ?-ketoglutarate-dependent enzymes in the maintenance of pluripotency during cellular reprogramming to induced pluripotent stem cells and in disruption of pluripotency during in vitro differentiation. The enzymatic function of many of these ?-ketoglutarate-dependent proteins is required for pluripotency acquisition and maintenance. A better understanding of their specific function will be essential in furthering our knowledge of pluripotency.

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Uncoupling the distinct functions of HP1 proteins during heterochromatin establishment and maintenance.

Project description:H3K9 methylation (H3K9me) marks transcriptionally silent genomic regions called heterochromatin. HP1 proteins are required to establish and maintain heterochromatin. HP1 proteins bind to H3K9me, recruit factors that promote heterochromatin formation, and oligomerize to form phase-separated condensates. We do not understand how HP1 protein binding to heterochromatin establishes and maintains transcriptional silencing. Here, we demonstrate that the S.pombe HP1 homolog, Swi6, can be completely bypassed to establish silencing at ectopic and endogenous loci when an H3K4 methyltransferase, Set1 and an H3K14 acetyltransferase, Mst2 are deleted. Deleting Set1 and Mst2 enhances Clr4 enzymatic activity, leading to higher H3K9me levels and spreading. In contrast, Swi6 and its capacity to oligomerize were indispensable during epigenetic maintenance. Our results demonstrate the role of HP1 proteins in regulating histone modification crosstalk during establishment and identifies a genetically separable function in maintaining epigenetic memory.

| S-EPMC10634687 | biostudies-literature

Uncoupling the distinct functions of HP1 proteins during heterochromatin establishment and maintenance

Project description:H3K9 methylation (H3K9me) marks transcriptionally silent genomic regions called heterochromatin. A conserved class of HP1 proteins are critically required to establish and maintain heterochromatin. HP1 proteins bind to H3K9me, recruit factors that promote heterochromatin formation, and oligomerize to form phase-separated condensates. We do not understand how HP1 protein binding to heterochromatin establishes and maintains transcriptional silencing. Here, we demonstrate that the S.pombe HP1 homolog, Swi6, can be completely bypassed to establish silencing at ectopic and endogenous loci when an H3K4 methyltransferase, Set1 and an H3K14 acetyltransferase, Mst2 are deleted. Deleting Set1 and Mst2 enhances Clr4 enzymatic activity, leading to higher H3K9me levels and increased spreading. In contrast, Swi6 and its capacity to oligomerize were indispensable during epigenetic maintenance. Our results demonstrate the role of HP1 proteins in regulating histone modification crosstalk during establishment and identifies a genetically separable function in maintaining epigenetic memory.

2023-09-26 | GSE244017 | GEO

Defining differentially methylated regions specific for the acquisition of pluripotency and maintenance in human pluripotent stem cells via microarray.

Project description:BackgroundEpigenetic regulation is critical for the maintenance of human pluripotent stem cells. It has been shown that pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, appear to have a hypermethylated status compared with differentiated cells. However, the epigenetic differences in genes that maintain stemness and regulate reprogramming between embryonic stem cells and induced pluripotent stem cells remain unclear. Additionally, differential methylation patterns of induced pluripotent stem cells generated using diverse methods require further study.MethodologyHere, we determined the DNA methylation profiles of 10 human cell lines, including 2 ESC lines, 4 virally derived iPSC lines, 2 episomally derived iPSC lines, and the 2 parental cell lines from which the iPSCs were derived using Illumina's Infinium HumanMethylation450 BeadChip. The iPSCs exhibited a hypermethylation status similar to that of ESCs but with distinct differences from the parental cells. Genes with a common methylation pattern between iPSCs and ESCs were classified as critical factors for stemness, whereas differences between iPSCs and ESCs suggested that iPSCs partly retained the parental characteristics and gained de novo methylation aberrances during cellular reprogramming. No significant differences were identified between virally and episomally derived iPSCs. This study determined in detail the de novo differential methylation signatures of particular stem cell lines.ConclusionsThis study describes the DNA methylation profiles of human iPSCs generated using both viral and episomal methods, the corresponding somatic cells, and hESCs. Series of ss-DMRs and ES-iPS-DMRs were defined with high resolution. Knowledge of this type of epigenetic information could be used as a signature for stemness and self-renewal and provides a potential method for selecting optimal pluripotent stem cells for human regenerative medicine.

| S-EPMC4177110 | biostudies-literature

Defining Differentiated Methylation Regions Especial for Pluripotency Acquisition and Maintenance in Human Stem Cell

Project description:Here, we determined the DNA methylation profiles of 12 human cell lines, including 2 ESC lines, 2 pESC lines,4 virally-delivered iPSC lines, 2 episomal-delivered iPSC lines, and 2 parent cell lines that iPSCs derived from using Illumina’s Infinium HumanMethylation450. The iPSCs exhibited a hypermethylation status similarly to ESCs but distinct differences from the parent cells. Genes of common methylation pattern between iPSCs and ESCs were regarded as critical factors for stemness, while differences existing between iPSCs and ESCs implied that iPSCs partly retained the parental characteristics and gained de novo methylation aberrances during cell reprogramming. No significant variant was identified between virally- and episomal- systems. De novo differentiated methylation regions as the signature of particular stem cell lines were figured out in detail in this study. 2 ESC lines, 2 pESC lines,4 virally-delivered iPSC lines, 2 episomal-delivered iPSC lines, and 2 parent cell lines that iPSCs derived from

2014-05-29 | E-GEOD-57992 | biostudies-arrayexpress

Mechanisms of functional promiscuity by HP1 proteins.

Project description:Heterochromatin protein 1 (HP1) proteins were originally identified as critical components in heterochromatin-mediated gene silencing and are now recognized to play essential roles in several other processes including gene activation. Several eukaryotes possess more than one HP1 paralog. Despite high sequence conservation, the HP1 paralogs achieve diverse functions. Further, in many cases, the same HP1 paralog is implicated in multiple functions. Recent biochemical studies have revealed interesting paralog-specific biophysical differences and unanticipated conformational versatility in HP1 proteins that may account for this functional promiscuity. Here we review these findings and describe a molecular framework that aims to link the conformational flexibility of HP1 proteins observed in vitro with their functional promiscuity observed in vivo.

| S-EPMC4077871 | biostudies-literature

Defining Differentiated Methylation Regions Especial for Pluripotency Acquisition and Maintenance in Human Stem Cell

2014-05-29 | GSE57992 | GEO

HP1? is not necessary for the structural maintenance of centromeric heterochromatin.

Project description:Heterochromatin protein 1 (HP1) was discovered as a protein essential for maintaining the silent transcriptional status of genes located within or close to centromeric regions of Drosophila chromosomes. Mammals express three variants of HP1; of these, HP1? is a direct homolog of Drosophila HP1. The prevailing view states that HP1 is a structural component of heterochromatin and is essential for compact DNA packaging. HP1 contains a chromodomain that binds to di- and- tri-methylated lysine 9 of histone H3. Additionally, it contains a chromoshadow domain that allows HP1 to dimerize and interact with other proteins. HP1 is thought to form "bridges" between neighboring rows of nucleosomes in heterochromatin. In mammalian cells, a significant portion of HP1? is located in the centromeric regions of chromosomes. In this study, we show that the majority of HP1? is removed from centromeres upon heat shock. This occurs without a loss of H3K9 trimethylation and does not correlate with a decompaction of centromeres. Furthermore, HP1? is not degraded and remains bound to chromatin. Therefore, it is likely that HP1? is simply redistributed to euchromatic regions. We propose that this redistribution is essential for reversal of the transcriptional status of euchromatic and heterochromatic compartments.

| S-EPMC3092686 | biostudies-literature

Geminin is required for the maintenance of pluripotency.

Project description:Pluripotency requires the expression of the three core transcriptions factors Oct4, Sox2 and Nanog, as well as further, complementary proteins. The geminin protein is part of this network, and was shown to play a role in the regulation of DNA replication, the control of the cell cycle, and the acquisition of neural fate. It is highly expressed in the early embryo, in particular the epiblast and the early neural ectoderm, and also in pluripotent embryonic stem cells. The genetic inactivation of geminin resulted in lethality after the first few cell divisions, and thus prohibited the outgrowth of pluripotent cells. We established embryonic stem cells allowing the deletion of the geminin gene by induction of of Cre-recombinase with tamoxifen. Here, we show that geminin deficiency quickly leads to a loss of pluripotency, and to differentiation into the mesendodermal direction with high Oct4/low Sox2 levels. Simultaneous loss of geminin and induction of the neural lineage resulted in immediate apoptosis. These results suggested that in early development geminin functions via the co-expressed Sox2 gene. We found that the stem cell enhancer SRR2 of Sox2 is occupied by the activating esBAF complex in the presence of geminin, but becomes epigenetically repressed in its absence by the Polycomb repressive complex PRC2. The importance of geminin for Sox2 expression also explains the absolute requirement for geminin during the induction of pluripotency by OSKM viruses. In summary, geminin is required for Sox2 expression, and thus for the maintenance of totipotency, pluripotency and the early neural lineage.

| S-EPMC3777968 | biostudies-literature

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