Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

Abstract

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

• Authors: Carole Le Coz, David N Nguyen, Chun Su, Brian E Nolan, Amanda V Albrecht, Suela Xhani, Di Sun, Benjamin Demaree, Piyush Pillarisetti, Caroline Khanna, Francis Wright, Peixin Amy Chen, Samuel Yoon, Amy L Stiegler, Kelly Maurer, James P Garifallou, Amy Rymaszewski, Steven H Kroft, Timothy S Olson, Alix E Seif, Gerald Wertheim, Struan F A Grant, Linda T Vo, Jennifer M Puck, Kathleen E Sullivan, John M Routes, Viktoria Zakharova, Anna Shcherbina, Anna Mukhina, Natasha L Rudy, Anna C E Hurst, T Prescott Atkinson, Titus J Boggon, Hakon Hakonarson, Adam R Abate, Joud Hajjar, Sarah K Nicholas, James R Lupski, James Verbsky, Ivan K Chinn, Michael V Gonzalez, Andrew D Wells, Alex Marson, Gregory M K Poon, Neil Romberg
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 218 Issue 7 (07 05 2021) ISSN: 1540-9538 [Electronic] United States
• PMID: 33951726 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 Le Coz et al.

Chemical References

• Chromatin
• Proto-Oncogene Proteins
• Trans-Activators
• proto-oncogene protein Spi-1

Topics

• Adolescent
• Adult
• Agammaglobulinemia (genetics)
• B-Lymphocytes (physiology)
• Cell Differentiation (genetics)
• Cell Line
• Child
• Child, Preschool
• Chromatin (genetics)
• Dendritic Cells (physiology)
• Female
• Gene Expression Regulation, Developmental (genetics)
• HEK293 Cells
• Hematopoiesis (genetics)
• Hematopoietic Stem Cells (physiology)
• Humans
• Infant
• Lymphopoiesis (genetics)
• Male
• Mutation (genetics)
• Precursor Cells, B-Lymphoid (physiology)
• Proto-Oncogene Proteins (genetics)
• Stem Cells (physiology)
• Trans-Activators (genetics)
• Young Adult