Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

RNAseq of organ-cultured human hair follicles exposed to MEKi (Cobimetinib)

ABSTRACT: EGFR/MEK inhibitor therapy induces a distinct inflammatory hair follicle response that includes a collapse of hair follicle immune privilege and differential modulation of IL-33 and IL-37 expression. Our findings suggest that successful future management of EGFRi/MEKi-induced folliculitis requires restoration of hair follicle immune privilege. In this RNAseq organ-cultured human hair follicles were directly exposed to MEKi (Cobimetinib) or the control DMSO (n=5 patients (6-8 hair follicles per patient)).

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Homo sapiens

SUBMITTER: Rachel Scholey

PROVIDER: E-MTAB-13454 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Human hair follicle organ culture: theory, application and perspectives.

Langan Ewan A EA Philpott Michael P MP Kloepper Jennifer E JE Paus Ralf R

Experimental dermatology 20151201 12

For almost a quarter of a century, ex vivo studies of human scalp hair follicles (HFs) have permitted major advances in hair research, spanning diverse fields such as chronobiology, endocrinology, immunology, metabolism, mitochondrial biology, neurobiology, pharmacology, pigmentation and stem cell biology. Despite this, a comprehensive methodological guide to serum-free human HF organ culture (HFOC) that facilitates the selection and analysis of standard HF biological parameters and points out b ...[more]

PMID: 26284830

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Project description:Increasing evidence suggests that microRNAs may play important roles in regulating self-renewal and differentiation in mammalian stem cells (SCs). Here, we explore this issue in skin. We first characterize microRNA expression profiles of skin SCs versus their committed proliferative progenies and identify a microRNA subset associating with “stemness”. Of these, miR-125b is dramatically downregulated in early SC-progeny. We engineer an inducible mice system and show that when miR-125b is sustained in SC-progenies, tissue balance is reversibly skewed towards stemness at the expense of epidermal, oil-gland and HF differentiation. Using gain-and-loss of function in vitro, we further implicate miR-125b as a repressor of SC differentiation. In vivo, transcripts repressed upon miR-125b induction are enriched >700% for predicted miR-125b targets normally downregulated upon SC-lineage commitment. We verify some of these miR-125b targets, and show that Blimp1 and VDR in particular can account for many tissue imbalances we see when miR-125b is deregulated. We used microarrays to compare the global miRNA expression profile of P4 stage hair follicle ORS cells from DTG (K14-rtTA,TRE-miR-125b) and control littermates. Hair follicle cells were isolated from P4 Backskin (Dox since P3 for 24hrs) of DTG (K14-rtTA/TRE-miR-125b/K14-H2BGFP), TRE (TRE-miR-125b/K14-H2BGFP), KrtA (K14-rtTA/K14-H2BGFP) as following: interfollicular epidermis sheet was pealed from hair follicle & dermis after dispase treatment.The hair follicle & dermis were first digested by collagenase (Sigma). Intact hair follicles were separated from dermal cells by low speed spinning (20g). The hair follicles were then digested by Trypsin and filtered by 40 µm cell strainers. The isolated hair follicle cells were FACS sorted. During FACS, cells were first gated against CD34 (endothelial cells), CD45 (immune cells), CD114 (melanocytes) and DAPI (dead cells). ORS cells were sorted from the remaining cells as α6HiGFPHi.

Project description:The Hos: HR-1 mouse strain (HR-1) is an autosomal resessive mutant strain which is widely used in pharmacological and dermatological studies in Japan. Although HR-1 mice have been believed to be Hr gene mutants based on their distinctive alopecia phenotype, there are no reports on either the genetic nature of the Hr gene or mechanism of alopecia. The present study clarified that the HR-1 mice carry a C to T transition in the Hr gene, which causes a proline to serin amino acid change in the functional domain of translated HR protein. It is well known that HR plays an important role in hair follicle regression, and loss of HR function triggers distinctive alopecia with the presence of premature apoptosis in the regressing hair follicle. However, the detailed function of HR protein is still uncertain. To clarify the mechanism by which HR dysfunction causes hair loss, here we performed microarray analysis on the mRNA samples obtained from the regressing hair follicles of the homozygous (HrHos / HrHos) and heterozygous (+/HrHos, control) Hr mutant mice using laser capture microdissection. Our results showed increased expression of apoptosis-related and cell-cycle-repressive genes and decreased expression of cell-cycle-promoting genes, suggesting inhibition of the cell cycle at G0/G1. These findings strongly suggest that the loss of HR function leads to high expression of cell cycle inhibitors, resulting in the hair loss with premature apoptosis in the hair matrix. Experiment Overall Design: Homozygous (HrHos / HrHos) and heterozygous (+/HrHos) Hr mutant mice of the same N1 littermates obtained from a male Hos: HR-1 mouse and a female heterozygous F1 offspring (+/HrHos) between an HR-1 mouse and an ICR mouse were used at day 14 postpartum. +/HrHos mice were used as controls because the Hr gene mutantion is autosomal recessive and the morphological appearance of +/HrHos is as same as that of wild-type mice. Four samples (two from +/HrHos and two from HrHos / HrHos) were analyzed. All RNA samples were extracted from hair follicles of dorsal skin using Laser capture microdissection.

Dataset Information

RNAseq of organ-cultured human hair follicles exposed to MEKi (Cobimetinib)

Publications

Human hair follicle organ culture: theory, application and perspectives.

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