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The epigenetic reader BRWD1 in peripheral adaptive immunity

Award Number: R01AI143778
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/10/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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The epigenetic reader BRWD1 in peripheral adaptive immunity - PROJECT SUMMARY Recently, we demonstrated that the lineage-restricted BROMO and WD40 domain containing epigenetic reader BRWD1 opens Igk and induces an epigenetic landscape that enables assembly of RAG proteins at Jk. We now report that BRWD1 has a much broader role in late B cell development. BRWD1 reshapes chromatin landscapes by closing enhancers of genes expressed early in B cell development and opening those of genes expressed in late stages. BRWD1 did not affect the expression of critical transcription factors (TFs). Rather, as demonstrated for IRF4, BRWD1 determines the sites they bind across the genome. BRWD1 differentially regulated over 7000 genes, repressing proliferative and inducing differentiation programs. Notably, BRWD1 coordinately repressed Myc and Myc target genes. Furthermore, in humans, BRWD1 mutations are associated with hypogammaglobulinemia. These data indicate that, in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B cell development. BRWD1 is first expressed in small pre-B cells. However, Brwd1 expression is higher in naïve follicular (FO) and in germinal center (GC) dark zone (DZ) cells. Analysis of genes differentially expressed in GC DZ and light zone (LZ) cells, compared to those differentially regulated by BRWD1 in small pre-B cells, predicts that BRWD1 represses the DZ program and induces the LZ program. Furthermore, differential genome-wide binding of BRWD1 in DZ and LZ cells suggests different functions in each GC subset. Immunizing Brwd1fl/fl x Aicda (AID)- Cre mice revealed that BRWD1 was required for normal antibody isotype switching and affinity maturation. Histologically, GCs were greatly reduced in both size, and number, and lacked follicular dendritic cells. Therefore, we hypothesize that BRWD1 regulates epigenetic states and enhancer landscapes critical for coordination of DZ and LZ transcriptional programs and GC function. We will test this hypothesis in the following Specific Aims: Aim 1. Determine the transcriptional regulation of normal germinal center responses. Aim 2. Determine the role of BRWD1 in adaptive immunity. Aim 3. Determine the role of BRWD1 in initiating GC responses and in maintaining FO B cell identity. !


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	5	5/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $487,845 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	5	12/16/2022	NON-COMPETING CONTINUATION	$487,845
														Subtotal = $487,845

Issue Date FY: 2022 ( Subtotal = $487,845 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	4	12/15/2021	NON-COMPETING CONTINUATION	$487,845
														Subtotal = $487,845

Issue Date FY: 2021 ( Subtotal = $487,845 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	3	12/22/2020	NON-COMPETING CONTINUATION	$487,845
														Subtotal = $487,845

Issue Date FY: 2020 ( Subtotal = $487,845 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	2	12/27/2019	NON-COMPETING CONTINUATION	$487,845
														Subtotal = $487,845

Issue Date FY: 2019 ( Subtotal = $487,845 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	1/10/2019	NEW	$487,845
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	1	3/7/2019	NEW	$0
														Subtotal = $487,845

Grand Total All Awards = $2,439,225

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The epigenetic reader BRWD1 in peripheral adaptive immunity

Award Number: R01AI143778

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/10/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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