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IRX5 promotes DNA damage repair and activation of hair follicle stem cells [ms_epidermis]

ABSTRACT: Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice display delayed onset of first postnatal anagen, with increased DNA damage and diminished HFSC proliferation. Through transcriptomic and epigenetic analysis, we discover the formation of open chromatin regions near key cell cycle progression- and DNA damage repair genes in Irx5-/- HFSC. We also identify DNA damage repair factors BRCA1 and BARD1 as IRX5 downstream targets. Inhibition of FGF18 kinase signaling partially rescues the anagen delay in Irx5-/- mice, indicating that the Irx5-/- HFSC quiescent phenotype is in part due to failure to suppress Fgf18 expression. Our findings identify IRX5 as a required promoter of DNA damage repair in HFSC activation and hair cycle initiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE201884 | GEO | 2022/11/01

REPOSITORIES: GEO

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IRX5 promotes DNA damage repair and activation of hair follicle stem cells (hfsc)

Project description:Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice display delayed onset of first postnatal anagen, with increased DNA damage and diminished HFSC proliferation. Through transcriptomic and epigenetic analysis, we discover the formation of open chromatin regions near key cell cycle progression- and DNA damage repair genes in Irx5-/- HFSC. We also identify DNA damage repair factors BRCA1 and BARD1 as IRX5 downstream targets. Inhibition of FGF18 kinase signaling partially rescues the anagen delay in Irx5-/- mice, indicating that the Irx5-/- HFSC quiescent phenotype is in part due to failure to suppress Fgf18 expression. Our findings identify IRX5 as a required promoter of DNA damage repair in HFSC activation and hair cycle initiation.

2023-04-05 | GSE202583 | GEO

IRX5 promotes DNA damage repair and activation of hair follicle stem cells [nhek_d]

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IRX5 promotes DNA damage repair and activation of hair follicle stem cells [ATAC-Seq]

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IRX5 promotes DNA damage repair and activation of hair follicle stem cells [NHEK RNA-Seq]

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FGF18 Signaling for Hair Cycle Resting Phase Determines Radioresistance of Hair Follicles by the Arrest of Hair Cycling

Project description:Telogen (resting phase) hair follicles are more radioresistant than anagen (growth phase) ones. Irradiation of BALB/c mice in the anagen phase with γ-rays at 6 Gy induced hair follicle dystrophy, whereas irradiation in the telogen phase induced the arrest of hair follicle elongation without any dystrophy after post-irradiation depilation. In contrast, FGF18 was highly expressed in the telogen hair follicles to maintain the telogen phase and also the quiescence of hair follicle stem cells. Therefore, the inhibition of FGF receptor signaling at telogen induced the dystrophy after post-irradiation depilation. In addition, the administration of recombinant FGF18 suppressed cell proliferation in the hair follicles and enhanced the repair of radiation-induced DNA damage, so FGF18 protected the anagen hair follicles against radiation damage to enhance hair regeneration. Moreover, FGF18 reduced the expression of cyclin B1 and cdc2 in the skin and FGF18 signaling induced G2/M arrest in the keratinocyte cell line HaCaT, although no obvious change of the expression of DNA repair genes was detected by DNA microarray analysis. These findings suggest that FGF18 signaling for the hair cycle resting phase causes radioresistance in telogen hair follicles by arresting the proliferation of hair follicle cells.

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BRCA1/BARD1 intrinsically disordered regions facilitate chromatin recruitment and ubiquitylation

Project description:BRCA1/BARD1 is a tumor suppressor E3 ubiquitin (Ub) ligase with roles in DNA damage repair and in transcriptional regulation. BRCA1/BARD1 RING domains interact with nucleosomes to facilitate mono-ubiquitylation of distinct residues on the C-terminal tail of histone H2A. These enzymatic domains constitute a small fraction of the heterodimer, raising the possibility of functional chromatin interactions involving other regions such as the BARD1 C-terminal domains that bind nucleosomes containing the DNA damage signal H2A K15-Ub and H4 K20me0, or portions of the expansive intrinsically disordered regions found in both subunits. Herein, we reveal novel interactions that support robust H2A ubiquitylation activity mediated through a high-affinity, intrinsically disordered DNA-binding region of BARD1. These interactions support BRCA1/BARD1 recruitment to chromatin and sites of DNA damage in cells and contribute to their survival. We also reveal distinct BRCA1/BARD1 complexes that depend on the presence of H2A K15-Ub, including a complex where a single BARD1 subunit spans adjacent nucleosome units. Our findings identify an extensive network of multivalent BARD1-nucleosome interactions that serve as a platform for BRCA1/BARD1-associated functions on chromatin.

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FGF18 affects hair cycle.

Project description:Fgf18 gene is strongly expressed in hair follicles of mouse dorsal skin during regressing (catagen) and resting (telogen) phases of hair cycle, but not in growth (anagen) phase. This study aims at identifying the effects of FGF18 local delivery on the anagen phase of hair cycle. To define genes affected by local delivery of FGF18 during anagen phase of hair cycle, we injected FGF18 protein subcutaneously into back skin of C3H/HeN mice on day 4 of depilation-induced anagen. As control PBS was injected in place of FGF18. After 24 h (61-d-old), total RNA was isolated from the back skin and purified to poly A RNA. The RNA samples were pooled for each group. Gene expression was analyzed by one-color analysis using single array for each group.

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Cooperative and antagonistic roles for Irx3 and Irx5 in cardiac morphogenesis and postnatal physiology

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2012-06-19 | E-GEOD-38826 | biostudies-arrayexpress

FGF18 affects hair cycle.

2017-05-15 | GSE29546 | GEO

BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis.

Project description:Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair pathway, and, together with BARD1, forms a heterodimer with ubiquitin E3 activity. The relevance of the BRCA1/BARD1 ubiquitin E3 activity for tumor suppression and DNA repair remains controversial and most efforts aimed to identify BRCA1/BARD1 ubiquitination substrates rely on indirect evidence. Here, we observed that the BRCA1/BARD1 ubiquitin E3 activity was not required for Homologous Recombination or resistance to Olaparib. Using TULIP2 methodology, which enables the direct identification of E3-specific ubiquitination substrates, we identified substrates for BRCA1/BARD1. We found that PCNA is ubiquitinated by BRCA1/BARD1 in unperturbed conditions independently of RAD18. PCNA ubiquitination by BRCA1/BARD1 avoids the formation of ssDNA gaps during DNA replication and promotes continuous DNA synthesis. These results address the controversy about the function of BRCA1/BARD1 E3 activity in Homologous Recombination.

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