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NFI Transcription Factors Govern Stem Cell Chromatin Accessibility and Guard Against Irreversible Hair Loss [ATAC-seq]

ABSTRACT: Tissue homeostasis and regeneration rely upon resident stem cells (SCs), whose behavior is regulated through niche-dependent crosstalk. The mechanisms underlying SC maintenance are still unfolding. Here, using hair follicles (HFs) as model and spatiotemporal gene ablation in mice, we uncover transcription factors (TFs) NFIB and NFIX as guardians of the process. Complete NFI ablation causes SC depletion and hair loss which resembles irreversible alopecia in humans, who intriguingly also display reduced NFI. Through single cell transcriptomics, ATAC- and ChIP-seq profiling, we uncover a key role for NFIB/NFIX in governing chromatin accessibility of HFSC master TFs . When NFIB/NFIX are genetically removed, the stemness epigenetic landscape is lost, as enhancers driving HFSC identity are decommissioned and those of epidermal differentiation and wound-repair are de-repressed. Together, our findings expose NFIB/NFIX as crucial rheostats of tissue homeostasis, functioning to safeguard the SC epigenome from a breach in lineage confinement that otherwise triggers irreversible tissue degeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE135144 | GEO | 2020/04/01

REPOSITORIES: GEO

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Project description:The Nuclear Factor I (NFI) family of transcription factors (TFs) plays key roles in cellular differentiation, proliferation, and homeostasis. As such, NFI family members engage in large number of interactions with other proteins and the chromatin. However, despite their well-established significance, the NFIs interactomes, their dynamics, and their functions have not been comprehensively examined. Here, we employed complementary omics-level techniques, i.e. interactomics (affinity purification mass spectrometry (AP-MS) and proximity-dependent biotinylation (BioID)), and chromatin immunoprecipitation sequencing (ChIP-Seq), to obtain a comprehensive view of the NFI proteins and their interactions. Our analyses included all four main NFI family members, and a less studied short isoform of NFIB (NFIB4), which lacks the DNA binding domain. We observed that, despite exhibiting some redundancy, each family member had unique high-confidence interactors and target genes, highlighting distinct roles within the transcriptional regulatory networks. The study revealed that NFIs interact with a large number of other TFs to co-regulate a broad range of regulatory networks and cellular processes. Notably, time-dependent proximity-labeling unveiled a highly dynamic nature of NFI protein-protein interaction networks and hinted at temporal modulation of NFI interactions. Furthermore, gene ontology (GO) enrichment analysis of NFI interactome and targetome revealed the involvement of NFIs in transcriptional regulation, chromatin organization, and cellular signaling pathways, and pathways related with cancer. Additionally, we observed that NFIB4 engages with proteins associated with mRNA regulation, which suggests that NFIs have roles beyond traditional DNA binding and transcriptional modulation. We propose that NFIs serve as pioneering TFs, playing critical roles in regulating other TFs and influencing a wide range of cellular processes. These insights into NFI protein-protein interactions and their dynamic, context-dependent nature provide a deeper understanding of gene regulation mechanisms and hint at the role of NFIs as master regulators.

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NFI Transcription Factors Govern Stem Cell Chromatin Accessibility and Guard Against Irreversible Hair Loss [ATAC-seq]

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