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1.
Science ; 385(6704): 91-99, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38963839

ABSTRACT

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in ß-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.


Subject(s)
Anemia, Sickle Cell , Antisickling Agents , Fetal Hemoglobin , Kruppel-Like Transcription Factors , Nerve Tissue Proteins , Animals , Humans , Mice , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Anemia, Sickle Cell/drug therapy , Anemia, Sickle Cell/metabolism , Antisickling Agents/chemistry , Antisickling Agents/pharmacology , Antisickling Agents/therapeutic use , Crystallography, X-Ray , Drug Discovery , Fetal Hemoglobin/genetics , Fetal Hemoglobin/metabolism , Kruppel-Like Transcription Factors/metabolism , Macaca fascicularis , Nerve Tissue Proteins/metabolism , Proteolysis/drug effects , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics
2.
bioRxiv ; 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38712281

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) - characterized by excess accumulation of fat in the liver - now affects one third of the world's population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.

3.
Cell Stem Cell ; 28(10): 1822-1837.e10, 2021 10 07.
Article in English | MEDLINE | ID: mdl-34129813

ABSTRACT

AXIN2 and LGR5 mark intestinal stem cells (ISCs) that require WNT/ß-Catenin signaling for constant homeostatic proliferation. In contrast, AXIN2/LGR5+ pericentral hepatocytes show low proliferation rates despite a WNT/ß-Catenin activity gradient required for metabolic liver zonation. The mechanisms restricting proliferation in AXIN2+ hepatocytes and metabolic gene expression in AXIN2+ ISCs remained elusive. We now show that restricted chromatin accessibility in ISCs prevents the expression of ß-Catenin-regulated metabolic enzymes, whereas fine-tuning of WNT/ß-Catenin activity by ZNRF3 and RNF43 restricts proliferation in chromatin-permissive AXIN2+ hepatocytes, while preserving metabolic function. ZNRF3 deletion promotes hepatocyte proliferation, which in turn becomes limited by RNF43 upregulation. Concomitant deletion of RNF43 in ZNRF3 mutant mice results in metabolic reprogramming of periportal hepatocytes and induces clonal expansion in a subset of hepatocytes, ultimately promoting liver tumors. Together, ZNRF3 and RNF43 cooperate to safeguard liver homeostasis by spatially and temporally restricting WNT/ß-Catenin activity, balancing metabolic function and hepatocyte proliferation.


Subject(s)
Liver , Ubiquitin-Protein Ligases/genetics , Animals , Cell Proliferation , Hepatocytes/metabolism , Liver/growth & development , Liver/metabolism , Mice , Stem Cells/metabolism , Ubiquitin-Protein Ligases/metabolism , Wnt Signaling Pathway , beta Catenin/metabolism
4.
Blood ; 137(21): 2920-2934, 2021 05 27.
Article in English | MEDLINE | ID: mdl-33512466

ABSTRACT

OBF1 is a specific coactivator of the POU family transcription factors OCT1 and OCT2. OBF1 and OCT2 are B cell-specific and indispensable for germinal center (GC) formation, but their mechanism of action is unclear. Here, we show by chromatin immunoprecipitation-sequencing that OBF1 extensively colocalizes with OCT1 and OCT2. We found that these factors also often colocalize with transcription factors of the ETS family. Furthermore, we showed that OBF1, OCT2, and OCT1 bind widely to the promoters or enhancers of genes involved in GC formation in mouse and human GC B cells. Short hairpin RNA knockdown experiments demonstrated that OCT1, OCT2, and OBF1 regulate each other and are essential for proliferation of GC-derived lymphoma cell lines. OBF1 downregulation disrupts the GC transcriptional program: genes involved in GC maintenance, such as BCL6, are downregulated, whereas genes related to exit from the GC program, such as IRF4, are upregulated. Ectopic expression of BCL6 does not restore the proliferation of GC-derived lymphoma cells depleted of OBF1 unless IRF4 is also depleted, indicating that OBF1 controls an essential regulatory node in GC differentiation.


Subject(s)
Germinal Center/metabolism , Octamer Transcription Factor-1/physiology , Octamer Transcription Factor-2/therapeutic use , Trans-Activators/therapeutic use , Transcription, Genetic/genetics , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Cell Line, Tumor , Chromatin Immunoprecipitation , Gene Ontology , HEK293 Cells , Humans , Lipopolysaccharides/pharmacology , Lymphoma, Non-Hodgkin/genetics , Lymphoma, Non-Hodgkin/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Octamer Transcription Factor-1/deficiency , Octamer Transcription Factor-1/genetics , Octamer Transcription Factor-2/deficiency , Octamer Transcription Factor-2/genetics , Proto-Oncogene Protein c-ets-1/analysis , RNA Interference , RNA, Small Interfering/genetics , Recombinant Proteins/metabolism , Trans-Activators/deficiency , Trans-Activators/genetics
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