Wdr5 Mediates Self-Renewal and Reprogramming via the Embryonic Stem Cell Core Transcriptional Network

Abstract

SUMMARY The embryonic stem (ES) cell transcriptional and epigenetic networks are critical for the maintenance of ES cell self-renewal. However, it remains unclear whether components of these networks functionally interact and if so, what factors mediate such interactions. Here we show that WD-repeat protein-5 (Wdr5), a core member of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated state and is a novel regulator of ES cell self-renewal. We demonstrate that Wdr5, an ‘effector’ of H3K4 methylation, interacts with the pluripotency transcription factor Oct4. Genome-wide protein localization and transcriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. We show that the Oct4-Sox2-Nanog circuitry and trxG cooperate in activating transcription of key self-renewal regulators. Furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS) cells. We propose an integrated model of transcriptional and epigenetic control, mediated by select trxG members, for maintenance of ES cell self-renewal and somatic cell reprogramming.

Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

“…Mechanistically, Kat8 has been found to regulate the ESC transcription network by functioning upstream to activate Nanog [25]. Interestingly, Wdr5, a shared component of the Kat8-containing complex and the MLL complex catalyzing H3K4 methylation [56], displays a phenotype similar to that of Kat8 when depleted in ESCs [57]. Given that Dpy30, another MLL complex component regulating H3K4 methylation, is dispensable for ESC self-renewal [58], it seems likely that the Kat8-containing complex mediates the Wdr5 function.…”

“…EBs [195] Histone acetyl-Wdr5 NA Reduced Failure [57] Enhanced primary NA ation/H3K4 efficiency [57] endoderm methylation differentiation [57] H3K9 Kmt1a/ NA Enhanced NA NA Normal development methylation Suv39h1 efficiency [74] [196] Kmt1c/ NA *Mildly reduced No effect [197] Defect in RA-induced Post-implantation G9a efficiency [74]. differentiation in vitro lethality (E8.5-9.5)…”

The Polycomb Protein Ezh2 Impacts on Induced Pluripotent Stem Cell Generation

“…Additionally, expression of Trithorax complex component WD repeat domain 5 (Wdr5), an effector of histone H3 lysine 4 (H3K4) methylation, is required for efficient iPS cell generation [38]. Furthermore, inhibition of the H3 lysine 79 (H3K79) methyltransferase DOT1L accelerates reprogramming and increases the frequency of iPS cells [22].…”

From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

“…For example, ESRRB, SALL4, TBX3, KLF4, KLF2 and REST have joined the ranks of TFs constituting the 'pluripotency network' [21,[27][28][29][30][31]. Moreover, non-coding RNAs such as miR-134, miR-296 and miR-470 have been shown to directly regulate Oct4, Nanog and Sox2 [32], while epigenetic modifiers such as PRDM14 and WDR5 also display overlapping regulatory functions with the core pluripotency factors [33,34]. Although understanding how these molecules are functionally integrated represents a complex task, iterations of regulatory networks have been generated on transcriptional [21,24,30,35] and posttranslational levels [36,37], while other studies have integrated data from multiple regulatory levels [38,39].…”