Abstract
SummaryCellular differentiation requires dramatic changes in chromatin organization, transcriptional regulation, and protein production. To understand the regulatory connections between these processes, we generated proteomic, transcriptomic, and chromatin accessibility data during differentiation of mouse embryonic stem cells (ESCs) into postmitotic neurons and found extensive associations between different molecular layers within and across differentiation time points. We observed that SOX2, as a regulator of pluripotency and neuronal genes, redistributes from pluripotency enhancers to neuronal promoters during differentiation, likely driven by changes in its protein interaction network. We identified ATRX as a major SOX2 partner in neurons, whose co-localization correlated with an increase in active enhancer marks and increased expression of nearby genes, which we experimentally confirmed for three loci. Collectively, our data provide key insights into the regulatory transformation of SOX2 during neuronal differentiation, and we highlight the significance of multi-omic approaches in understanding gene regulation in complex systems.
Highlights
Cellular plasticity is a fundamental property of cells to dynamically respond to changes in their environment, which is apparent in its most dramatic form during development and differentiation
Multi-omics Factor Analysis (MOFA) Reveals Three Latent Factors Underlying Differentiation Heterogeneity To gain a comprehensive and unbiased overview of the molecular events during neuronal differentiation, we used a differentiation protocol of mouse embryonic stem cells (ESCs) to postmitotic neurons (Bibel et al, 2007) that yields about 84%–88% neurons on day 10 (Figure S1A) and performed ATAC-seq, RNA-seq, and MS-based proteomics at several time points (Figure 1A and Table S1)
Data were collected for ESCs, exit from pluripotency after LiF removal, neural progenitors after stimulation with retinoic acid, and mature neurons
Summary
Cellular plasticity is a fundamental property of cells to dynamically respond to changes in their environment, which is apparent in its most dramatic form during development and differentiation. TFs themselves are typically regulated as downstream effectors of cell signaling pathways, through post-translational modifications, or through induction of their own expression Their binding to DNA can be regulated by chromatin accessibility (Kaplan et al, 2011; Klemm et al, 2019; Pique-Regi et al, 2011), histone tail modifications (Mikkelsen et al, 2007), and the availability of their interaction partners (Adams and Workman, 1995; Deplancke, 2009), often in a gene or locus-specific manner. To understand differentiation at the molecular level, we need to understand all levels of TF regulation and their interactions and mutual interplay
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