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NFI transcription factors provide chromatin access to maintain stem cell identity while preventing unintended lineage fate choices.

ABSTRACT: Tissue homeostasis and regeneration rely on resident stem cells (SCs), whose behaviour is regulated through niche-dependent crosstalk. The mechanisms underlying SC identity are still unfolding. Here, using spatiotemporal gene ablation in murine hair follicles, we uncover a critical role for the transcription factors (TFs) nuclear factor IB (NFIB) and IX (NFIX) in maintaining SC identity. Without NFI TFs, SCs lose their hair-regenerating capability, and produce skin bearing striking resemblance to irreversible human alopecia, which also displays reduced NFIs. Through single-cell transcriptomics, ATAC-Seq and ChIP-Seq profiling, we expose a key role for NFIB and NFIX in governing super-enhancer maintenance of the key hair follicle SC-specific TF genes. When NFIB and NFIX are genetically removed, the stemness epigenetic landscape is lost. Super-enhancers driving SC identity are decommissioned, while unwanted lineages are de-repressed ectopically. Together, our findings expose NFIB and 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.

SUBMITTER: Adam RC

PROVIDER: S-EPMC7367149 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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NFI transcription factors provide chromatin access to maintain stem cell identity while preventing unintended lineage fate choices.

Adam Rene C RC Yang Hanseul H Ge Yejing Y Infarinato Nicole R NR Gur-Cohen Shiri S Miao Yuxuan Y Wang Ping P Zhao Yilin Y Lu Catherine P CP Kim Jeong E JE Ko Joo Y JY Paik Seung S SS Gronostajski Richard M RM Kim Jaehwan J Krueger James G JG Zheng Deyou D Fuchs Elaine E

Nature cell biology 20200511 6

Tissue homeostasis and regeneration rely on resident stem cells (SCs), whose behaviour is regulated through niche-dependent crosstalk. The mechanisms underlying SC identity are still unfolding. Here, using spatiotemporal gene ablation in murine hair follicles, we uncover a critical role for the transcription factors (TFs) nuclear factor IB (NFIB) and IX (NFIX) in maintaining SC identity. Without NFI TFs, SCs lose their hair-regenerating capability, and produce skin bearing striking resemblance t ...[more]

PMID: 32393888

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Project description:INTRODUCTION:Alcohol and tobacco use are common among U.S. women, yet if used during pregnancy these substances present significant preventable risks to prenatal and perinatal health. Because use of alcohol and tobacco often continue into the first trimester and beyond, especially among women with unintended pregnancies, effective evidence-based approaches are needed to decrease these risk behaviors. This study was designed to test the efficacy of CHOICES Plus, a preconception intervention for reducing the risk of alcohol- and tobacco-exposed pregnancies (AEPs and TEPs). STUDY DESIGN:RCT with two intervention groups: CHOICES Plus (n=131) versus Brief Advice (n=130). Data collected April 2011 to October 2013. Data analysis finalized February 2016. SETTING/PARTICIPANTS:Settings were 12 primary care clinics in a large Texas public healthcare system. Participants were women who were non-sterile, non-pregnant, aged 18-44 years, drinking more than three drinks per day or more than seven drinks per week, sexually active, and not using effective contraception (N=261). Forty-five percent were smokers. INTERVENTION:Interventions were two CHOICES Plus sessions and a contraceptive visit or Brief Advice and referral to community resources. MAIN OUTCOME MEASURES:Primary outcomes were reduced risk of AEP and TEP through 9-month follow-up. RESULTS:In intention-to-treat analyses across 9 months, the CHOICES Plus group was more likely than the Brief Advice group to reduce risk of AEP with an incidence rate ratio of 0.620 (95% CI=0.511, 0.757) and absolute risk reduction of -0.233 (95% CI=-0.239, -0.226). CHOICES Plus group members at risk for both exposures were more likely to reduce TEP risk (incidence rate ratio, 0.597; 95% CI=0.424, 0.840 and absolute risk reduction, -0.233; 95% CI=-0.019, -0.521). CONCLUSIONS:CHOICES Plus significantly reduced AEP and TEP risk. Addressing these commonly co-occurring risk factors in a single preconception program proved both feasible and efficacious in a low-income primary care population. Intervening with women before they become pregnant could shift the focus in clinical practice from treatment of substance-exposed pregnancies to prevention of a costly public health concern. TRIAL REGISTRATION:This study is registered at clinicaltrials.gov NCT01032772.

Dataset Information

NFI transcription factors provide chromatin access to maintain stem cell identity while preventing unintended lineage fate choices.

Publications

NFI transcription factors provide chromatin access to maintain stem cell identity while preventing unintended lineage fate choices.

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