A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation-Reference-Cited by-同舟云学术

A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation

Published:2023-08-29 Issue:11 Volume:220 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Ralvenius William T.¹^ORCID,Mungenast Alison E.¹^ORCID,Woolf Hannah¹^ORCID,Huston Margaret M.¹^ORCID,Gillingham Tyler Z.¹^ORCID,Godin Stephen K.¹^ORCID,Penney Jay¹^ORCID,Cam Hugh P.¹^ORCID,Gao Fan¹^ORCID,Fernandez Celia G.²^ORCID,Czako Barbara²^ORCID,Lightfoot Yaima²^ORCID,Ray William J.²^ORCID,Beckmann Adrian²^ORCID,Goate Alison M.³⁴⁵^ORCID,Marcora Edoardo³⁴⁵^ORCID,Romero-Molina Carmen³⁴⁵^ORCID,Ayata Pinar³⁴⁶^ORCID,Schaefer Anne³⁴⁷^ORCID,Gjoneska Elizabeta¹⁸^ORCID,Tsai Li-Huei¹⁹^ORCID

Affiliation:

1. Picower Institute for Learning and Memory, Massachusetts Institute of Technology 1 Department of Brain and Cognitive Sciences, , Cambridge, MA, USA

2. The University of Texas MD Anderson Cancer Center 3 The Neurodegeneration Consortium, Therapeutics Discovery Division, , Houston, TX, USA

3. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai 4 Nash Family Department of Neuroscience, , New York, NY, USA

4. Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai 5 , New York, NY, USA

5. Icahn School of Medicine at Mount Sinai 6 Department of Genetics and Genomic Sciences, , New York, NY, USA

6. Advanced Science Research Center at the Graduate Center, Neuroscience Initiative, City University of New York 7 , New York, NY, USA

7. Max Planck Institute for Biology of Ageing 8 , Cologne, Germany

8. National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park 9 Neurobiology Laboratory, , Durham, NC, USA

9. Broad Institute of MIT and Harvard 2 , Cambridge, MA, USA

Abstract

Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer’s disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse models of AD, A11 ameliorated neuroinflammation, loss of neuronal integrity, AD pathology, and improved cognitive performance. This study uncovers a novel class of anti-inflammatory molecules with therapeutic potential for neurodegenerative disorders.

Funder

National Institutes of Health

JPB Foundation

Swiss National Science Foundation

Alzheimer’s Association

University of Texas MD Anderson Cancer Center

National Cancer Institute

Cancer Prevention and Research Institute of Texas

Robert A. and Renee E. Belfer Family Foundation

Picower Institute for Learning and Memory

Halis Family Foundation

Publisher