Deletion of Mediator (Med1) induces epidermal fate in dental epithelial stem cells
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PROVIDER: PRJNA449381 | ENA |
REPOSITORIES: ENA
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Project description:Cell fates are defined by specific transcriptional program. We developed a mouse model, in which transcriptional program for ectoderm cell fate is altered in tooth and skin. Previously, we showed that genomic deletion of one subunit of Mediator complex, Mediator 1 (Med1) in vivo regenerate ectopic hair in incisors by disrupting Notch mediated enamel epithelial differentiation. However, precise process and molecular mechanism to induce epidermal fate are not clear. Med1 deficient dental epithelial stem cells exerts transcriptional program for skin epithelia reminiscent of the pattern in the skin. Epidermal transcripts were first induced prior to hair genes during dental epithelial differentiation, resemble to the pattern of embryonic developmental process of the skin. Hair genes was specifically induced at the anagen stage synchronized with hair cycling in the skin. Epidermal program was also induced in cultured adult stem cells called dental epithelial stem cell (DESC) that is derived from micro-dissected Med1 KO cervical loop tissues that are essential for continuous regeneration of mouse incisors. Gene expression profiles for the primary DESC with colony forming capability revealed that Med1 deletion suppressed Tgfb signaling by reducing the expression of ligands (Tgfb1, Inhibin ba), receptors and their extracellular targets such as Ctgf. Med1 deletion also induced Tgfb regulated reprogramming transcription factor, Klf4 that also known to drive transcription for epidermal genes. TGFb signaling was also suppressed in Med1 null epidermis in skin, in which epidermal fate was induced in hair follicle keratinocytes. Med1 silencing blocked expression of TGFb1 and suppressed both basal and recombinant TGFb induced Smad2/3 mediated transcription of TGFb target genes in vitro. These results demonstrate that Med1 deletion enhances epidermal transcriptional program in adult stem cells through regulation of TGFb signaling.
2018-12-31 | GSE112884 | GEO
Project description:Cell fate is defined by specific transcriptional program. Here, we provide evidence that the transcriptional coactivator, Mediator 1 (MED1), is critical in determining the cell fate of ectodermal epithelia. MED1 ablation disrupted enamel formation and generated hair adjacent to the incisors. Deletion of MED1 altered the differentiation of dental epithelia to one expressing epidermal and hair genes similar to the skin. The cellular switch from dental to epidermal/hair lineage was characterized by abnormalities in MED1 deficient dental epithelial stem cells residing in cervical loop. MED1 deficiency caused a failure of dental epithelial stem cells to commit to the dental stratum intermedium regulated by Notch signaling. Instead, MED1 deficient cells retained stem cell potentials expressing Sox2. These cells were eventually adopted an epidermal fate probably through calcium provided through capillary networks, which is originally utilized for enamel formation. Our results demonstrate that MED1 regulates Sox2/Notch1 regulated cell lineage determination in dental epithelia. Our study also shows a potential to regenerate hairs by using genetically engineered dental tissues or cells outside of the skin. n=3 WT and KO (each sample contain dissected dental tissues from 3 mice combined)
2013-09-23 | E-GEOD-50503 | biostudies-arrayexpress
Project description:Cell fate is defined by specific transcriptional program. Here, we provide evidence that the transcriptional coactivator, Mediator 1 (MED1), is critical in determining the cell fate of ectodermal epithelia. MED1 ablation disrupted enamel formation and generated hair adjacent to the incisors. Deletion of MED1 altered the differentiation of dental epithelia to one expressing epidermal and hair genes similar to the skin. The cellular switch from dental to epidermal/hair lineage was characterized by abnormalities in MED1 deficient dental epithelial stem cells residing in cervical loop. MED1 deficiency caused a failure of dental epithelial stem cells to commit to the dental stratum intermedium regulated by Notch signaling. Instead, MED1 deficient cells retained stem cell potentials expressing Sox2. These cells were eventually adopted an epidermal fate probably through calcium provided through capillary networks, which is originally utilized for enamel formation. Our results demonstrate that MED1 regulates Sox2/Notch1 regulated cell lineage determination in dental epithelia. Our study also shows a potential to regenerate hairs by using genetically engineered dental tissues or cells outside of the skin. n=4 WT and KO (each group contains dissected dental tissues from 3 mice combined)
2013-09-23 | E-GEOD-50502 | biostudies-arrayexpress
Project description:Cell fate is defined by specific transcriptional program. Here, we provide evidence that the transcriptional coactivator, Mediator 1 (MED1), is critical in determining the cell fate of ectodermal epithelia. MED1 ablation disrupted enamel formation and generated hair adjacent to the incisors. Deletion of MED1 altered the differentiation of dental epithelia to one expressing epidermal and hair genes similar to the skin. The cellular switch from dental to epidermal/hair lineage was characterized by abnormalities in MED1 deficient dental epithelial stem cells residing in cervical loop. MED1 deficiency caused a failure of dental epithelial stem cells to commit to the dental stratum intermedium regulated by Notch signaling. Instead, MED1 deficient cells retained stem cell potentials expressing Sox2. These cells were eventually adopted an epidermal fate probably through calcium provided through capillary networks, which is originally utilized for enamel formation. Our results demonstrate that MED1 regulates Sox2/Notch1 regulated cell lineage determination in dental epithelia. Our study also shows a potential to regenerate hairs by using genetically engineered dental tissues or cells outside of the skin. n=3 WT and KO (each sample contain dissected dental tissues from 3 mice combined)
2013-09-23 | E-GEOD-50501 | biostudies-arrayexpress
Project description:Cell fate is defined by specific transcriptional program. Here, we provide evidence that the transcriptional coactivator, Mediator 1 (MED1), is critical in determining the cell fate of ectodermal epithelia. MED1 ablation disrupted enamel formation and generated hair adjacent to the incisors. Deletion of MED1 altered the differentiation of dental epithelia to one expressing epidermal and hair genes similar to the skin. The cellular switch from dental to epidermal/hair lineage was characterized by abnormalities in MED1 deficient dental epithelial stem cells residing in cervical loop. MED1 deficiency caused a failure of dental epithelial stem cells to commit to the dental stratum intermedium regulated by Notch signaling. Instead, MED1 deficient cells retained stem cell potentials expressing Sox2. These cells were eventually adopted an epidermal fate probably through calcium provided through capillary networks, which is originally utilized for enamel formation. Our results demonstrate that MED1 regulates Sox2/Notch1 regulated cell lineage determination in dental epithelia. Our study also shows a potential to regenerate hairs by using genetically engineered dental tissues or cells outside of the skin.
2013-09-23 | GSE50503 | GEO
Project description:Cell fate is defined by specific transcriptional program. Here, we provide evidence that the transcriptional coactivator, Mediator 1 (MED1), is critical in determining the cell fate of ectodermal epithelia. MED1 ablation disrupted enamel formation and generated hair adjacent to the incisors. Deletion of MED1 altered the differentiation of dental epithelia to one expressing epidermal and hair genes similar to the skin. The cellular switch from dental to epidermal/hair lineage was characterized by abnormalities in MED1 deficient dental epithelial stem cells residing in cervical loop. MED1 deficiency caused a failure of dental epithelial stem cells to commit to the dental stratum intermedium regulated by Notch signaling. Instead, MED1 deficient cells retained stem cell potentials expressing Sox2. These cells were eventually adopted an epidermal fate probably through calcium provided through capillary networks, which is originally utilized for enamel formation. Our results demonstrate that MED1 regulates Sox2/Notch1 regulated cell lineage determination in dental epithelia. Our study also shows a potential to regenerate hairs by using genetically engineered dental tissues or cells outside of the skin.
2013-09-23 | GSE50502 | GEO
Project description:Cell fate is defined by specific transcriptional program. Here, we provide evidence that the transcriptional coactivator, Mediator 1 (MED1), is critical in determining the cell fate of ectodermal epithelia. MED1 ablation disrupted enamel formation and generated hair adjacent to the incisors. Deletion of MED1 altered the differentiation of dental epithelia to one expressing epidermal and hair genes similar to the skin. The cellular switch from dental to epidermal/hair lineage was characterized by abnormalities in MED1 deficient dental epithelial stem cells residing in cervical loop. MED1 deficiency caused a failure of dental epithelial stem cells to commit to the dental stratum intermedium regulated by Notch signaling. Instead, MED1 deficient cells retained stem cell potentials expressing Sox2. These cells were eventually adopted an epidermal fate probably through calcium provided through capillary networks, which is originally utilized for enamel formation. Our results demonstrate that MED1 regulates Sox2/Notch1 regulated cell lineage determination in dental epithelia. Our study also shows a potential to regenerate hairs by using genetically engineered dental tissues or cells outside of the skin.
2013-09-23 | GSE50501 | GEO
Project description:Cell fates are defined by specific transcriptional program. Previously, we developed a unique stem cell regeneration mouse model, in which transcriptional program for ectoderm organs such as tooth and skin is switched. Genomic deletion of one subunit of Mediator complex, Med1, resulted in defective enamel regeneration, in which dental stem cells were inhibited from undergoing transcriptional program for dental fate. In stead, they exerted skin program for both hair and epidermis, and post-natally regenerate ectopic hairs in the incisors. Here, we report that Med1 also modulates epidermal and hair cell fates in the skin. Med1 ablation further enhanced epidermal and sebocyte fates, and accelerated injury induced epidermal regeneration. However, it blunted hair fate resulting in hair loss in the skin. Ablation of Med1 increased the number of isthmus stem cells and epidermal stem cells, which regenerate epidermis during cutaneous wound healing process. Med1 deficiency also constitutively activated these stem cells and increased their proliferation. Microarray profiling indicated that Med1 deletion causes activation of β-catenin and suppression of TGFβ signaling. Med1 deficiency induced the expression of β-catenin target genes to control cell fate and proliferation. It also decreased TGFβ expression in interfollicular epidermis. Med1 deficiency increased the proliferation and migration of epidermal cells, and induced nuclear translocation of β-catenin, and decreased TGFβ1 expression in vitro. Our finding together with previous observations demonstrated that Med1 governs ectoderm cell fate in both tooth and skin. Med1 ablation blunts hair fate but induces epidermal and sebocyte cell fates to accelerated injury induced epidermal regeneration in the skin. Accelerated regeneration is derived from constitutive activation of epidermal stem cells accompanied with increased proliferation and migration of their progeny by balancing of β-catenin induced growth promoting and TGFβ mediated growth inhibitory activities in the skin.
2017-06-30 | GSE89967 | GEO
Project description:Postnatal cell fate has been postulated to be primarily determined by the local tissue microenvironment. Here, we found that Mediator 1 (Med1) dependent epigenetic mechanisms dictate tissue-specific lineage commitment and progression of dental epithelia. Deletion of Med1, a key component of the Mediator complex linking enhancer activities to gene transcription, provokes a tissue extrinsic lineage shift, causing hair generation in the dental environment. Med1 deficiency gives rise to unusual hair growth via primitive cellular aggregates on incisors. Mechanistically, we found that Med1 establishes super-enhancers that control enamel lineage transcription factors in dental stem cells and their progenies. However, Med1 deficiency reshapes the enhancer landscapes and causes a switch from the dental epithelial transcriptional program towards hair and epidermis on incisors in vivo, and in dental epithelial stem cells in vitro. Med1 loss also provokes an increase in the number and size of enhancers. Interestingly, control dental epithelia already exhibit enhancers for hair and epidermal key transcription factors; these expand in size and transform into super-enhancers upon Med1 loss suggesting that these epigenetic mechanisms cause the transcriptomic and phenotypic shift towards epidermal and hair lineages. Thus, we propose a role for Med1 in safeguarding lineage specific enhancers, highlight the central role of enhancer accessibility and usage in lineage reprogramming and provide new insights into ectodermal regeneration. Duplicate Chip-seq for dental tisses from head region of cervical loop (CLH) containing dental epithelial stem cells and tail region (CLT) including progenies that were dissected from mandible of 4 week old conditional Krt14CreMed1 knockout (cKO) mice or littermate control (Ctrl) mice. Chip-seq was conducted by using antibodies against Mediator 1 (Med1) and H3K27ac (H3).
2023-06-22 | GSE221565 | GEO
Project description:Transcriptional coactivator Mediator complex facilitates transcription of various transcription factors. Previously, we have generated Med1 conditional null mice, where a critical subunit of Mediator, Med1, is removed from keratinocytes. Here we present evidence that ablation of Med1 accelerated epidermal regeneration after injury. As bulge keratinocyte stem cells are important contributors to regenerate epidermis, we first analyzed properties of stem cells in Med1 null mice. BrdU long retaining analysis revealed that deletion of Med1 still maintained quiescence of bulge keratinocyte stem cells, despite of general hyperplasia observed in Med1 deficient keratinocytes. Gene expression analysis demonstrated that a series of niche matrix proteins decreased in Med1 deficient keratinocytes. In contrast, the expression of stem cell marker Sox9 was not altered, suggesting stem cells are present but activated because of abnormal niche surrounding stem cells. In addition, Med1 deletion suppressed injury induced inflammatory reaction, which indirectly regulates epidermal regeneration. We also indicated that TGFβ1 significantly decreased in both bulge and epidermal keratinocytes upon Med1 deletion. Our study demonstrates that coactivator Med1 has a critical role to maintain bulge stem cells and epidermal regeneration presumably through regulation in TGFβ signaling. n=4 WT and KO (each sample contain RNA from one mouse)
2014-01-01 | E-GEOD-50671 | biostudies-arrayexpress