Going up the hill: chromatin‐based barriers to epigenetic reprogramming

Abstract

The establishment and maintenance of cellular identity are crucial during development and tissue homeostasis. Epigenetic mechanisms based largely on DNA methylation and histone modifications serve to reinforce and safeguard differentiated cell states. Somatic cell nuclear transfer (SCNT) or transcription factors such as Oct4, Sox2, Klf4, c-MYC (OSKM) can erase somatic cell identity and reprogram the cells to a pluripotent state. In doing so, reprogramming must reset the chromatin landscape, silence somatic-specific gene expression programs, and, in their place, activate the pluripotency network. In this viewpoint, we consider the major chromatinbased barriers for reprogramming of somatic cells to pluripotency. Among these, repressive chromatin modifications such as DNA methylation, H3K9 methylation, variant histone deposition, and histone deacetylation generally block the activation of pluripotency genes. In contrast, active transcription-associated chromatin marks such as DOT1L-catalyzed H3K79 methylation, FACT-mediated histone turnover, active enhancer SUMOylation, and EP300/CBP bromodomain-mediated interactions act to maintain somatic-specific gene expression programs. We highlight how genetic or chemical inhibition of both types of barriers can enhance the kinetics and/ or efficiency of reprogramming. Understanding the mechanisms by which these barriers function provides insight into how chromatin marks help maintain cell identity.

Deciphering the roadmap of in vivo reprogramming toward pluripotency

“…Regarding the rest of the pancreatic cell types, endocrine cells appear to be resistant to OSKM reprogramming, while ductal cells acquire a reactive molecular profile similar to ductal cells in CER-treated pancreas. It is possible that each cell type requires different periods of OSKM activation to surrender their somatic identity, probably reflecting the potency of epigenetic barriers ( Arabacı et al., 2021 ).…”

“…Cellular reprogramming is an inefficient process due, at least in part, to the existence of multiple cell-autonomous barriers, such as tumor suppressors, chromatin regulators, transcription factors, signaling pathways, and microRNAs ( Arabacı et al., 2021 ; Haridhasapavalan et al., 2020 ). Various studies have tried to untangle the complex cascade of molecular and epigenetic events occurring during in vitro reprogramming as well as to define intermediate states ( Brambrink et al., 2008 ; Chronis et al., 2017 ; O’Malley et al., 2013 ; Polo et al., 2012 ; Stadtfeld et al., 2008 ; Zviran et al., 2019 ).…”

Deciphering the roadmap of in vivo reprogramming towards pluripotency

“…Regarding the rest of the pancreatic cell types, endocrine cells appear to be resistant to OSKM reprogramming, while ductal cells acquire a reactive molecular profile similar to ductal cells in cerulein-treated pancreas. It is possible that each cell type requires different periods of OSKM activation to surrender their somatic identity, probably reflecting the potency of epigenetic barriers (Arabacı et al, 2021).…”

“…Cellular reprogramming is an inefficient process due, at least in part, to the existence of multiple cell-autonomous barriers, such as tumour suppressors, chromatin regulators, transcription factors, signalling pathways and micro RNAs (Arabacı et al, 2021; Haridhasapavalan et al, 2020). Various studies have tried to untangle the complex cascade of molecular and epigenetic events occurring during in vitro reprogramming as well as to define intermediate states (Brambrink et al, 2008; Chronis et al, 2017; O’Malley et al, 2013; Polo et al, 2012; Stadtfeld et al, 2008; Zviran et al, 2019).…”

LMCD1 facilitates the induction of pluripotency via cell proliferation, metabolism, and epithelial‐mesenchymal transition

“…The successful acquisition of human iPSCs opens a door to establish disease models and drug discovery in clinical treatment without ethical concerns (Grskovic et al, 2011; Shi et al, 2017; S. S. C. Hung, khan et al, 2017). Fast forward to today, however, how to overcome the barriers in the process of somatic cell reprogramming is still a challenging issue and restrict the development of iPSCs in regenerative medicine (Arabaci et al, 2021; Ebrahimi, 2015; Haridhasapavalan et al, 2020). Many transcription factors, such as NANOG, LIN28, PBX1, and GLIS1, were found to enhance the efficiency by either combining with OSKM or replacing several of OSKM (Dey et al, 2022; Jiang et al, 2019; J. Yu et al, 2007; Li et al, 2020).…”