Abstract
Embryonic stem cells (ESCs) are pluripotent and have unlimited self-renewal capacity. Although pluripotency and differentiation have been examined extensively, the mechanisms responsible for self-renewal are poorly understood and are believed to involve an unusual cell cycle, epigenetic regulators and pluripotency-promoting transcription factors. Here we show that B-MYB, a cell cycle regulated phosphoprotein and transcription factor critical to the formation of inner cell mass, is central to the transcriptional and co-regulatory networks that sustain normal cell cycle progression and self-renewal properties of ESCs. Phenotypically, B-MYB is robustly expressed in ESCs and induced pluripotent stem cells (iPSCs), and it is present predominantly in a hypo-phosphorylated state. Knockdown of B-MYB results in functional cell cycle abnormalities that involve S, G2 and M phases, and reduced expression of critical cell cycle regulators like ccnb1 and plk1. By conducting gene expression profiling on control and B-MYB deficient cells, ChIP-chip experiments, and integrative computational analyses, we unraveled a highly complex B-MYB-mediated transcriptional network that guides ESC self-renewal. The network encompasses critical regulators of all cell cycle phases and epigenetic regulators, pluripotency transcription factors, and differentiation determinants. B-MYB along with E2F1 and c-MYC preferentially co-regulate cell cycle target genes. B-MYB also co-targets genes regulated by OCT4, SOX2 and NANOG that are significantly associated with stem cell differentiation, embryonic development, and epigenetic control. Moreover, loss of B-MYB leads to a breakdown of the transcriptional hierarchy present in ESCs. These results coupled with functional studies demonstrate that B-MYB not only controls and accelerates cell cycle progression in ESCs it contributes to fate decisions and maintenance of pluripotent stem cell identity.
Highlights
All complex organisms contain stem cells with abilities to selfrenew indefinitely and differentiate into one or many types of specialized cell types
As reported in our previous publication, B-MYB is highly abundant in embryonic stem cells (ESCs), but here, we show for the first time that it is highly expressed in induced Pluripotent stem cells (PSCs) (iPSCs) at levels similar to those seen in ESCs (Figure 1A)
To better define how B-MYB target genes are regulated in ESCs, we identified genes co-targeted by B-MYB, OCT4, SOX2 and Nanog (OSN, Figure 7A and Table S1)
Summary
All complex organisms contain stem cells with abilities to selfrenew indefinitely and differentiate into one or many types of specialized cell types. These properties foster organismal development and promote cell replacement and organ repair in vivo. Pluripotent stem cells (PSCs), in particular, differentiate to all cell types of an embryo proper and may serve as an inexhaustible source of cell progeny useful for regenerative medicine. Experimentally-derived PSCs exhibit greater interline variation and differences in germ-line transmission than ESCs, iPSC lines may be more immunologically suited for regenerative medicine and disease modeling [5,6,7,8,9] [10,11]
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