NCoR/SMRT co-repressors cooperate with c-MYC to create an epigenetic barrier to somatic cell reprogramming

Abstract

Somatic cell reprogramming by exogenous factors requires cooperation with transcriptional co-activators and co-repressors to effectively remodel the epigenetic environment. How this interplay is regulated remains poorly understood. Here, we demonstrate that NCoR/SMRT co-repressors bind to pluripotency loci to create a barrier to reprogramming with the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC), and consequently, suppressing NCoR/SMRT significantly enhances reprogramming efficiency and kinetics. The core epigenetic subunit of the NCoR/SMRT complex, histone deacetylase 3 (HDAC3), contributes to the effects of NCoR/SMRT by inducing histone deacetylation at pluripotency loci. Among the Yamanaka factors, recruitment of NCoR/SMRT-HDAC3 to genomic loci is mostly facilitated by c-MYC. Hence, we describe how c-MYC is beneficial for the early phase of reprogramming but deleterious later. Overall, we uncover a role for NCoR/SMRT co-repressors in reprogramming and propose a dual function for c-MYC in this process.

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

“…Elevations in PPARg, SMRT, and NCOR which all interact to control downstream adipocyte fate and function, glucose handling, insulin sensitivity, mitochondrial oxidative capacity, and thermogenesis, were also found. [43,49] [36,50] [33] [51][52][53]. Thus, as inferred from the calorimetry data, there is upregulation of transcriptional machinery capable of increasing energy production and glucose utilization within the VAT of SG mice.…”

miR-203 imposes an intrinsic barrier during cellular reprogramming by targeting NFATC2

“…Cellular reprogramming is executed by complex gene regulatory networks ultimately leading to stable epigenetic modifications that determine a pluripotent cell state (Schmidt & Plath, 2012, Takahashi, 2014, Takahashi & Yamanaka, 2006. The induction of cellular reprogramming for specific transcription factors typically results in stress responses that limit the efficacy of this process, including senescence, p53-and CDKN2-pathways as well as epigenetic barriers (Banito, Rashid et al, 2009, Gascon, Masserdotti et al, 2017, Haridhasapavalan, Raina et al, 2020, Kawamura, Suzuki et al, 2009, Marion, Strati et al, 2009, Utikal, Polo et al, 2009, Zhuang, Li et al, 2018. Despite the advances in the last decade, reprogramming from somatic cells is still an inefficient process, limiting the application of this technology in regenerative medicine.…”

Wdr5, Brca1 and Bard1 link the DNA damage response to the mesenchymal-to-epithelial transition during early reprogramming

“…The strongest correlations are 180 observed between the Ncor1 -Oct4 pair and a triplet consisting of Wdr5, Brca1 and Bard1. Ncor1 181 was recently shown to physically interact with Myc and Oct4 (Zhuang et al, 2018), but the 182 functional relationships between Wdr5, Brca1 and Bard1 were unknown. We performed siRNA 183 deconvolution experiments measuring the number of Sall4-positive colonies of three independent 184 siRNAs for Wdr5, Brca1 and Bard1 to exclude off-target effects.…”