Role of the Epigenetic Regulator HP1γ in the Control of Embryonic Stem Cell Properties

Abstract

The unique properties of embryonic stem cells (ESC) rely on long-lasting self-renewal and their ability to switch in all adult cell type programs. Recent advances have shown that regulations at the chromatin level sustain both ESC properties along with transcription factors. We have focused our interest on the epigenetic modulator HP1γ (Heterochromatin Protein 1, isoform γ) that binds histones H3 methylated at lysine 9 (meH3K9) and is highly plastic in its distribution and association with the transcriptional regulation of specific genes during cell fate transitions. These characteristics of HP1γ make it a good candidate to sustain the ESC flexibility required for rapid program changes during differentiation. Using RNA interference, we describe the functional role of HP1γ in mouse ESC. The analysis of HP1γ deprived cells in proliferative and in various differentiating conditions was performed combining functional assays with molecular approaches (RT-qPCR, microarray). We show that HP1γ deprivation slows down the cell cycle of ESC and decreases their resistance to differentiating conditions, rendering the cells poised to differentiate. In addition, HP1γ depletion hampers the differentiation to the endoderm as compared with the differentiation to the neurectoderm or the mesoderm. Altogether, our results reveal the role of HP1γ in ESC self-renewal and in the balance between the pluripotent and the differentiation programs.

Differentiation-Independent Fluctuation of Pluripotency-Related Transcription Factors and Other Epigenetic Markers in Embryonic Stem Cell Colonies

“…This may correspond to spontaneous differentiation that can marginally occur within an ESC colony. Our suggestion corresponds to the experiments of Caillier et al [41], showing that depletion of HP1g in ESCs decreases their resistance to differentiation. Moreover, cells with downregulated HP1g undergo differentiation to endoderm with lower efficiency compared with maturation into neuroectoderm and mesoderm [41].…”

“…Our suggestion corresponds to the experiments of Caillier et al [41], showing that depletion of HP1g in ESCs decreases their resistance to differentiation. Moreover, cells with downregulated HP1g undergo differentiation to endoderm with lower efficiency compared with maturation into neuroectoderm and mesoderm [41]. These data illustrate the importance of nuclear patterns and specific levels of HP1 protein subtypes for maintaining the pluripotency of ESCs [20].…”

“…These data illustrate the importance of nuclear patterns and specific levels of HP1 protein subtypes for maintaining the pluripotency of ESCs [20]. Moreover, it is evident that the balance between pluripotent and differentiated ESCs is maintained not only by transcription factors, including Oct4, Nanog, and c-myc, but also by several epigenetic markers, including H3K9me3, H3K27me3, and HP1 subtypes [20,21,41].…”

Subcellular Localization of ENS-1/ERNI in Chick Embryonic Stem Cells

“…Western-blot results in Figure 5C show that the protein content decreased to become quite undetectable 24 h after retinoic acid addition and was maintained at this residual level after 48 h. In the same samples the expression level of HP1γ was not affected by differentiation (Fig. 5C) in agreement with previous observations in mouse ES cells [12]. These results are in accordance with the known regulation of the promoter of Ens-1 [8].…”

HP1γ expression is elevated in prostate cancer and is superior to Gleason score as a predictor of biochemical recurrence after radical prostatectomy

“…Genes important in embryogenesis frequently play a role in cancer [2]. One such gene, heterochromatin protein 1 gamma (HP1γ), is critically involved in chromatin packaging [3] and demonstrates altered expression during development and cell differentiation [4-6]. …”