The epigenetic reader BRD4 controls stem cell identity

A better understanding of the mechanisms that regulate ESC identity is needed to fulfill the promise of ESCs in regenerative medicine. Transcription factors and chromatin regulators control the ability of embryonic stem cells (ESCs) to self-renew and remain undifferentiated. An epigenetic reader called BRD4 acts at the boundary between transcription and chromatin remodeling: it binds to acetylated histone tails and recruits RNA Polymerase specifically at key stem cell genes. Genetic and chemical inhibition of BRD4 results in ESCs differentiation towards the neuro-ectodermal lineage. This study shed light on the mechanisms that regulate ESCs identity and could be exploited therapeutically for tissue regeneration and cell differentiation.

HFSP Long-Term Fellow Raffaella Di Micco and colleagues
authored on Mon, 02 February 2015

The ability of ESCs to self-renew in culture and to differentiate into the three germ layers depends on a set of transcription factors and an unusual open chromatin structure that allows prompt gene activation. BRD4 belongs to the Bromodomain and extra-terminal domain family of proteins and binds acetylated histones to activate gene expression. Instrumental to our study has been the availability of small molecules that can enter the cells and displace BRD4 from chromatin. Following chemical and genetic inhibition of BRD4, ESCs undergo changes in colony morphology and lose the expression of key stem cell genes. Combining cell and molecular biology approaches, together with next generation sequencing methods, we discovered that BRD4 binds to large clusters of enhancers (known also as super-enhancers) localized at cell identity genes. BRD4 facilitates the recruitment of the Mediator complex, CDK9 (catalytic subunit of the pTEF-b elongation complex) and Pol II at super-enhancers thus positively regulating the transcriptional elongation of SE-associated key embryonic stem cell factors such as NANOG, PRDM14, OCT4. Raffaella Di Micco  discovered that BRD4 inhibition results in defective elongation of SE-associated gene transcripts, loss of self-renewal ability and pluripotency of ESCs, and consequently, commitment to the neuroectodermal lineage (see figure for details).

This discovery has important therapeutic applications as BRD4 can be used to increase and perhaps even partially replace the “cocktail” of four embryonic transcription factors that have been used to ‘reprogram’ somatic cells into embryonic-like cells (induced pluripotent stem cells). Inhibiting BRD4 could also increase the efficiency of conversion of stem cells into neuronal progenitors—perhaps to fulfill the promise of personalized regenerative therapies. Moreover, consistent with the idea that cancer cells may adopt programs that are important for stem cell identity and during embryogenesis, BRD4 has been found to regulate the expression of known oncogenic drivers in many hematopoietic and solid tumors, it has been exploited as a target for cancer therapy.

Reference

Control of Embryonic Stem Cell Identity by BRD4-Dependent Transcriptional Elongation of Super-Enhancer-Associated Pluripotency Genes. Raffaella Di Micco*, Barbara Fontanals-Cirera, Vivien Low, Panagiotis Ntziachristos,  Stephanie K. Yuen, Claudia D. Lovell, Igor Dolgalev, Yoshiya Yonekubo, Guangtao Zhang, Elena Rusinova, Guillermo Gerona-Navarro, Marta Canamero, Michael Ohlmeyer, Iannis Aifantis, Ming-Ming Zhou, Aristotelis Tsirigos* and Eva Hernando*. Cell Reports, 2014 Oct 9;9(1):234-47. doi: 10.1016/j.celrep.2014.08.055. Epub 2014 Sep 26. * corresponding author.

Pubmed link