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Published on: October 27, 2020
MAB21L4 regulates the TGF-β-induced expression of target genes in epidermal keratinocytes
Tomohiro Ogami1, Yusuke Tamura1, Kim Toss1
1Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Abstract:
Smad proteins transduce signals downstream of transforming growth factor-β (TGF-β) and are one of the factors that regulate the expression of genes related to diseases affecting the skin. In the present study, we identified MAB21L4, also known as male abnormal 21 like 4 or C2orf54, as the most up-regulated targets of TGF-β and Smad3 in differentiated human progenitor epidermal keratinocytes using chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq). We found that TGF-β induced expression of the barrier protein involucrin (encoded by the IVL gene). Transcriptional activity of the IVL promoter induced by TGF-β was inhibited by MAB21L4 siRNAs. Further analysis revealed that MAB21L4 siRNAs also down-regulated the expression of several target genes of TGF-β. MAB21L4 protein was located mainly in the cytosol, where it was physically bound to Smad3 and a transcriptional corepressor c-Ski. siRNAs for MAB21L4 did not inhibit the binding of Smad3 to their target genomic regions but down-regulated the acetylation of histone H3 lys 27 (H3K27ac), an active histone mark, near the Smad3 binding regions. These findings suggest that TGF-β-induced MAB21L4 up-regulates the gene expression induced by TGF-β, possibly through the inhibition of c-Ski via physical interaction in the cytosol.
Insights
Transforming growth factor-β (TGF-β) signaling regulates skin cell genes. MAB21L4, a key target, enhances TGF-β-induced gene expression by interacting with Smad3 and inhibiting c-Ski in the cytosol.
Area of Science:
- Molecular Biology
- Cell Biology
- Dermatology
Background:
- Smad proteins mediate transforming growth factor-β (TGF-β) signaling, crucial for skin gene regulation.
- Dysregulation of TGF-β signaling is implicated in various skin diseases.
Purpose of the Study:
- To identify novel TGF-β/Smad3 target genes in human epidermal keratinocytes.
- To elucidate the role of MAB21L4 in TGF-β-induced gene expression and skin biology.
Main Methods:
- Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) were employed.
- Small interfering RNAs (siRNAs) were used to knockdown MAB21L4 expression.
- Co-immunoprecipitation and Western blotting were utilized to study protein interactions.
Main Results:
- MAB21L4 was identified as a significantly upregulated target of TGF-β/Smad3 in keratinocytes.
- MAB21L4 knockdown inhibited TGF-β-induced expression of involucrin (IVL) and other target genes.
- MAB21L4 protein interacts with Smad3 and c-Ski in the cytosol, affecting H3K27ac levels near Smad3 binding sites without altering Smad3 binding.
Conclusions:
- TGF-β-induced MAB21L4 plays a critical role in promoting TGF-β-mediated gene expression in keratinocytes.
- MAB21L4 may regulate gene expression by inhibiting the transcriptional corepressor c-Ski through cytosolic interaction.
- These findings offer insights into the molecular mechanisms of TGF-β signaling in skin homeostasis and disease.
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