Pluripotency factors regulate the onset of Hox cluster activation in the early embryo

Abstract

Pluripotent cells are a transient population of the mammalian embryo dependent on transcription factors, such as OCT4 and NANOG, which maintain pluripotency while suppressing lineage specification. However, these factors are also expressed during early phases of differentiation, and their role in the transition from pluripotency to lineage specification is largely unknown. We found that pluripotency factors play a dual role in regulating key lineage specifiers, initially repressing their expression and later being required for their proper activation. We show that Oct4 is necessary for activation of HoxB genes during differentiation of embryonic stem cells and in the embryo. In addition, we show that the HoxB cluster is coordinately regulated by OCT4 binding sites located at the 3′ end of the cluster. Our results show that core pluripotency factors are not limited to maintaining the precommitted epiblast but are also necessary for the proper deployment of subsequent developmental programs.

HOX genes in stem cells: Maintaining cellular identity and regulation of differentiation

“…Very recently it was shown that respective processes here were linked to HOX gene regulation (Tiana et al, 2022). The pluripotency factor OCT4 turned out to be important for maintaining HOX genes silent in the stage of pluripotency.…”

“…An FGF2 activation was found to activate the downstream kinase Src, a non-receptor tyrosine kinase that in turn activates MEK1 / 2 (Mitogen-activated protein kinase 1) resulting in differentiation and/or increased proliferation particularly of mesodermal ASCs ( Ma et al, 2019 ). Very recently it was shown that respective processes here were linked to HOX gene regulation ( Tiana et al, 2022 ). The pluripotency factor OCT4 turned out to be important for maintaining HOX genes silent in the stage of pluripotency.…”

“…Upon lineage commitment however, OCT4 switches from a repressor to an activator being required for the proper activation of HOX genes. Especially the genes of the HOXB cluster are coordinately regulated by OCT4 binding sites located at the 3′ end of the cluster ( Tiana et al, 2022 ).…”

Dynamic DNA methylation turnover at the exit of pluripotency epigenetically primes gene regulatory elements for hematopoietic lineage specification

“…2b) . For example, there were distinct clusters of H3K27me3 marked genes and regulatory elements, including clusters of homeobox ( Hox ) genes 47 known to be repressed by Polycomb repressive complex 2 (PRC2) and PRC1 in embryonic stem cells (Supplemental Fig. 2b) 48,49 .…”

Activator-blocker model of transcriptional regulation by pioneer-like factors

“…The dual role of Pou5f3 and Nanog in activating early zygotic genes and blocking premature transcription provides an immediate parallel to the biological roles of their mammalian homologues. Oct4/Pou5f1 and Nanog regulate the seemingly opposite processes of pluripotency maintenance and cell lineage decisions in mammalian embryos and ES cells [26][27][28][29][30] . Although zebrafish Pou5f3 is not equivalent to Oct4/Pou5f1 in terms of nucleosome-binding and reprogramming capacity 31 , Pou5f3 and Oct4 recognize the same motifs and colocalize with Nanog in the respective systems.…”