Abstract
Histones modulate gene expression by chromatin compaction, regulating numerous processes such as differentiation. However, the mechanisms underlying histone degradation remain elusive. Human embryonic stem cells (hESCs) have a unique chromatin architecture characterized by low levels of trimethylated histone H3 at lysine 9 (H3K9me3), a heterochromatin-associated modification. Here we assess the link between the intrinsic epigenetic landscape and ubiquitin-proteasome system of hESCs. We find that hESCs exhibit high expression of the ubiquitin-conjugating enzyme UBE2K. Loss of UBE2K upregulates the trimethyltransferase SETDB1, resulting in H3K9 trimethylation and repression of neurogenic genes during differentiation. Besides H3K9 trimethylation, UBE2K binds histone H3 to induce its polyubiquitination and degradation by the proteasome. Notably, ubc-20, the worm orthologue of UBE2K, also regulates histone H3 levels and H3K9 trimethylation in Caenorhabditis elegans germ cells. Thus, our results indicate that UBE2K crosses evolutionary boundaries to promote histone H3 degradation and reduce H3K9me3 repressive marks in immortal cells.
Highlights
Embryonic stem cells (ESCs) can replicate indefinitely while retaining their potential to differentiate into all cell lineages[1,2]
We find that the ubiquitin-conjugating enzyme E2 K (UBE2K), known as huntingtin-interacting protein 2 (HIP2), is upregulated in human ESCs (hESCs) compared with their differentiated counterparts
We found 4 E2 enzymes (i.e., UBE2C, UBE2G1, UBE2K and UBE2O) increased in hESCs when compared with their neural progenitor cell (NPC) and neuronal counterparts (Supplementary Table 1)
Summary
Embryonic stem cells (ESCs) can replicate indefinitely while retaining their potential to differentiate into all cell lineages[1,2]. Regulators of histone modifications and chromatin compaction are required for ESC differentiation, including the polycomb repressive complex 1 (PRC1)[9,10] In these lines, huntingtin protein (HTT) binds and inhibits SETDB1, a methyltransferase that trimethylates lysine 9 of histone H3. The ubiquitin-proteasome system has a central role in the immortality and cell fate decisions of pluripotent stem cells[16,17,18,19,20,21,22] Given their endogenous chromatin structure signature, ESCs could provide a novel paradigm to discover epigenetic regulatory mechanisms and their impact on differentiation. For this purpose, we ask whether the intrinsic ubiquitin-proteasome system of hESCs impinge on their epigenetic landscape. Our results provide a link between the ubiquitin-proteasome system and histone regulation in both ESCs and germ cells
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