Faculty Collaboration Database

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients. J Exp Med 2021 Jul 05;218(7)

Date

05/06/2021

Pubmed ID

33951726

Pubmed Central ID

PMC8105723

DOI

10.1084/jem.20201750

Scopus ID

2-s2.0-85105296806 (requires institutional sign-in at Scopus site)   30 Citations

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.

Author List

Le Coz C, Nguyen DN, Su C, Nolan BE, Albrecht AV, Xhani S, Sun D, Demaree B, Pillarisetti P, Khanna C, Wright F, Chen PA, Yoon S, Stiegler AL, Maurer K, Garifallou JP, Rymaszewski A, Kroft SH, Olson TS, Seif AE, Wertheim G, Grant SFA, Vo LT, Puck JM, Sullivan KE, Routes JM, Zakharova V, Shcherbina A, Mukhina A, Rudy NL, Hurst ACE, Atkinson TP, Boggon TJ, Hakonarson H, Abate AR, Hajjar J, Nicholas SK, Lupski JR, Verbsky J, Chinn IK, Gonzalez MV, Wells AD, Marson A, Poon GMK, Romberg N

Authors

Steven Howard Kroft MD Chair, Professor in the Pathology department at Medical College of Wisconsin
Amy Rymaszewski PhD Research Scientist I in the Pediatrics department at Medical College of Wisconsin
James Verbsky MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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