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Your search keyword '"Co-Repressor Proteins chemistry"' showing total 2 results
Start Over Descriptor "Co-Repressor Proteins chemistry" Journal nature communications
2 results on '"Co-Repressor Proteins chemistry"'

1. ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism.

Author

Li J, Galbo PM Jr, Gong W, Storey AJ, Tsai YH, Yu X, Ahn JH, Guo Y, Mackintosh SG, Edmondson RD, Byrum SD, Farrar JE, He S, Cai L, Jin J, Tackett AJ, Zheng D, and Wang GG

Subjects
Acetylation, Animals, Carcinogenesis, Cell Differentiation, Cell Proliferation, Cell Transformation, Neoplastic, Disease Models, Animal, Enhancer Elements, Genetic genetics, Gene Expression Regulation, Leukemic, Genome, Human, HEK293 Cells, Hematopoietic Stem Cells metabolism, Histones metabolism, Humans, Leukemia, Myeloid, Acute genetics, Mice, Inbred BALB C, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Oncogene Proteins, Fusion metabolism, Protein Binding, Protein Domains, Transcription Factors metabolism, Mice, Cell Cycle Proteins chemistry, Cell Cycle Proteins metabolism, Chromatin metabolism, Chromosomal Proteins, Non-Histone chemistry, Chromosomal Proteins, Non-Histone metabolism, Co-Repressor Proteins chemistry, Co-Repressor Proteins metabolism, DNA-Binding Proteins chemistry, DNA-Binding Proteins metabolism, Leukemia, Myeloid, Acute pathology, Lysine Acetyltransferase 5 metabolism
Abstract

Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-'reading' bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

Published
2021
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2. A molecular switch regulating transcriptional repression and activation of PPARγ.

Author

Shang J, Mosure SA, Zheng J, Brust R, Bass J, Nichols A, Solt LA, Griffin PR, and Kojetin DJ

Subjects
Apoproteins chemistry, Apoproteins metabolism, Binding Sites, Co-Repressor Proteins chemistry, Crystallography, X-Ray, HEK293 Cells, Humans, Ligands, Magnetic Resonance Spectroscopy, Mutation, Nuclear Receptor Coactivators chemistry, Nuclear Receptor Coactivators metabolism, PPAR gamma agonists, PPAR gamma genetics, Protein Binding, Protein Conformation, Structure-Activity Relationship, Transcription, Genetic, Benzamides metabolism, Co-Repressor Proteins metabolism, PPAR gamma chemistry, PPAR gamma metabolism, Pyridines metabolism
Abstract

Nuclear receptor (NR) transcription factors use a conserved activation function-2 (AF-2) helix 12 mechanism for agonist-induced coactivator interaction and NR transcriptional activation. In contrast, ligand-induced corepressor-dependent NR repression appears to occur through structurally diverse mechanisms. We report two crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) in an inverse agonist/corepressor-bound transcriptionally repressive conformation. Helix 12 is displaced from the solvent-exposed active conformation and occupies the orthosteric ligand-binding pocket enabled by a conformational change that doubles the pocket volume. Paramagnetic relaxation enhancement (PRE) NMR and chemical crosslinking mass spectrometry confirm the repressive helix 12 conformation. PRE NMR also defines the mechanism of action of the corepressor-selective inverse agonist T0070907, and reveals that apo-helix 12 exchanges between transcriptionally active and repressive conformations-supporting a fundamental hypothesis in the NR field that helix 12 exchanges between transcriptionally active and repressive conformations.

Published
2020
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