@article {1005,
	title = {Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.},
	journal = {J Exp Med},
	volume = {218},
	year = {2021},
	month = {2021 Jul 05},
	abstract = {<p>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{\textquoteright}s critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.</p>},
	issn = {1540-9538},
	doi = {10.1084/jem.20201750},
	author = {Le Coz, Carole and Nguyen, David N and Su, Chun and Nolan, Brian E and Albrecht, Amanda V and Xhani, Suela and Sun, Di and Demaree, Benjamin and Pillarisetti, Piyush and Khanna, Caroline and Wright, Francis and Chen, Peixin Amy and Yoon, Samuel and Stiegler, Amy L and Maurer, Kelly and Garifallou, James P and Rymaszewski, Amy and Kroft, Steven H and Olson, Timothy S and Seif, Alix E and Wertheim, Gerald and Grant, Struan F A and Vo, Linda T and Puck, Jennifer M and Sullivan, Kathleen E and Routes, John M and Zakharova, Viktoria and Shcherbina, Anna and Mukhina, Anna and Rudy, Natasha L and Hurst, Anna C E and Atkinson, T Prescott and Boggon, Titus J and Hakonarson, Hakon and Abate, Adam R and Hajjar, Joud and Nicholas, Sarah K and Lupski, James R and Verbsky, James and Chinn, Ivan K and Gonzalez, Michael V and Wells, Andrew D and Marson, Alex and Poon, Gregory M K and Romberg, Neil}
}
