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Function of human & mouse Beta-globin locus control regions

Award Number: R37DK044746
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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DESCRIPTION (provided by applicant): Our genetic, molecular and biochemical analyses of ß-globin gene regulation have yielded novel and surprising results, including that the locus control region (LCR) is not required to initiate or propagate the "open" chromatin structure of the locus or confer stage-specific expression of the ß-like globin genes. In its native location, the primary role of the LCR is to enhance the transition from basal to activated transcription. We now propose to gain further insights into the molecular basis for initiating and propagating the chromatin and transcription states of the ß-globin locus during erythropoiesis. Our Specific Aims include: 1. Define epigenetic features including histone modifications, sequence co-localization, DNA methylation and candidate trans-acting factors involved in the initiation and propagation of active and silent states of the ß-globin locus. We will test the hypothesis that the ß-globin "domain" is larger and more dynamic than formerly appreciated, and that specific sequences, factors and epigenetic modifications are involved in the initiation and propagation of active and silent states of the locus. Initial studies, in collaboration with Dr. X-D Fu (UCSD) who developed the highly sensitive DNA Selection and Ligation (DSL) array-based method, will focus on a 1mb region of human chromosome 11 (h11) centered on the LCR, using a currently available array. We will design and build a similar array for analysis of the mouse locus. 2. Determine the role of cis- acting regulatory elements, transcription and cellular background on domains of histone modifications, factor binding and sequence co-localization in the ß-globin locus. We will use targeted mutation analyses in ES cell derived mice and our h11 transfer system to investigate several hypotheses regarding the regulation of ß-globin gene expression. The effects of mutations on the epigenetic states of the locus, including factor binding, histone modifications and sequence interactions, will be determined by DSL analyses in stage-specific erythroid cells from mutant mice and in cell lines containing WT and modified h11s passed through different cellular backgrounds. Correlation of these results with activation state defined by primary transcript FISH, HS formation and the degree and extent of generalized DNase sensitivity will address several models of ß-globin gene regulation. 3. Identify novel genes involved in erythroid maturation and ß-globin gene expression. We will perform unbiased, genome-wide siRNA screens in the well- characterized G1E-ER cells and in ES derived erythroid progenitor (ES-EP) lines to identify novel factors involved in regulating ß-globin gene expression and erythroid maturation. The screen makes use of a lentiviral siRNA library comprised of a redundant set of siRNAs for each known mouse gene. We propose several strategies for the validation, identification and prioritization of candidate siRNAs, as well as for the biochemical and functional analysis of genes identified.


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: 2019 ( Subtotal = -$9,232 )
2019	2016	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	1/30/2019	EXTENSION WITH OR WITHOUT FUNDS	-$9,232
														Subtotal = -$9,232

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	3/1/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $817,022 )
2016	2016	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	4/13/2016	EXTENSION WITH OR WITHOUT FUNDS	$817,022
														Subtotal = $817,022

Issue Date FY: 2015 ( Subtotal = $883,022 )
2015	2015	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	3/31/2015	NON-COMPETING CONTINUATION	$883,022
														Subtotal = $883,022

Issue Date FY: 2014 ( Subtotal = $975,422 )
2014	2014	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	4/9/2014	NON-COMPETING CONTINUATION	$975,422
														Subtotal = $975,422

Issue Date FY: 2013 ( Subtotal = $880,827 )
2013	2013	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	22	5/16/2013	NON-COMPETING CONTINUATION	$53,106
2013	2013	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	3/19/2013	NON-COMPETING CONTINUATION	$735,321
2013	2013	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	22	9/6/2013	SUPPLEMENT FOR EXPANSION	$92,400
														Subtotal = $880,827

Issue Date FY: 2012 ( Subtotal = $796,078 )
2012	2012	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	011	21	8/17/2012	EXTENSION WITH OR WITHOUT FUNDS	$796,078
2012	2012	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	010	21	8/16/2012	EXTENSION WITH OR WITHOUT FUNDS	-$796,078
2012	2012	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	21	3/27/2012	EXTENSION WITH OR WITHOUT FUNDS	$796,078
2012	2011	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	007	20	8/9/2012	NON-COMPETING CONTINUATION	$660,652
2012	2011	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	20	8/8/2012	NON-COMPETING CONTINUATION	-$660,652
2012	2011	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	3/26/2012	NON-COMPETING CONTINUATION	$0
2012	2010	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	19	8/8/2012	NON-COMPETING CONTINUATION	-$667,327
2012	2010	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	009	19	8/9/2012	NON-COMPETING CONTINUATION	$667,327
2012	2009	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	18	8/8/2012	NON-COMPETING CONTINUATION	-$654,433
2012	2009	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	18	8/9/2012	NON-COMPETING CONTINUATION	$654,433
2012	2008	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	17	8/8/2012	NON-COMPETING CONTINUATION	-$635,372
2012	2008	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	008	17	8/9/2012	NON-COMPETING CONTINUATION	$635,372
														Subtotal = $796,078

Issue Date FY: 2011 ( Subtotal = $660,652 )
2011	2011	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	20	5/24/2011	NON-COMPETING CONTINUATION	$42,042
2011	2011	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	1/5/2011	NON-COMPETING CONTINUATION	$618,610
2011	2010	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Trans-NIH Recovery Act Research Support	000	18	11/2/2010	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $660,652

Issue Date FY: 2010 ( Subtotal = $767,314 )
2010	2010	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Trans-NIH Recovery Act Research Support	000	18	11/25/2009	SUPPLEMENT FOR EXPANSION	$99,987
2010	2010	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Kidney Diseases, Urology and Hematology Research	001	19	3/25/2010	NON-COMPETING CONTINUATION	$667,327
														Subtotal = $767,314

Issue Date FY: 2009 ( Subtotal = $654,433 )
2009	2009	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Kidney Diseases, Urology and Hematology Research	000	18	4/7/2009	NON-COMPETING CONTINUATION	$654,433
														Subtotal = $654,433

Issue Date FY: 2008 ( Subtotal = $635,372 )
2008	2008	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Kidney Diseases, Urology and Hematology Research	000	17	2/14/2008	NON-COMPETING CONTINUATION	$635,372
														Subtotal = $635,372

Issue Date FY: 2007 ( Subtotal = $693,764 )
2007	2007	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Kidney Diseases, Urology and Hematology Research	000	16	3/22/2007	COMPETING CONTINUATION	$693,764
														Subtotal = $693,764

Issue Date FY: 2006 ( Subtotal = $717,493 )
2006	2006	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Kidney Diseases, Urology and Hematology Research	000	15	2/14/2006	NON-COMPETING CONTINUATION	$717,493
														Subtotal = $717,493

Issue Date FY: 2005 ( Subtotal = $715,442 )
2005	2005	FRED HUTCHINSON CANCER RESEARCH CENTER	1124 COLUMBIA STREET	SEATTLE	WA	98104	KING	USA	Kidney Diseases, Urology and Hematology Research	000	14	1/13/2005	NON-COMPETING CONTINUATION	$715,442
														Subtotal = $715,442

Issue Date FY: 2004 ( Subtotal = $696,687 )
2004	2004	FRED HUTCHINSON CANCER RESEARCH CENTER	1124 COLUMBIA STREET	SEATTLE	WA	98104	KING	USA	Kidney Diseases, Urology and Hematology Research	000	13	12/31/2003	NON-COMPETING CONTINUATION	$696,687
														Subtotal = $696,687

Issue Date FY: 2003 ( Subtotal = $678,101 )
2003	2003	FRED HUTCHINSON CANCER RESEARCH CENTER	1124 COLUMBIA STREET	SEATTLE	WA	98104	KING	USA	Kidney Diseases, Urology and Hematology Research	000	12		NON-COMPETING CONTINUATION	$678,101
														Subtotal = $678,101

Issue Date FY: 2002 ( Subtotal = $708,347 )
2002	2002	FRED HUTCHINSON CANCER RESEARCH CENTER	1124 COLUMBIA STREET	SEATTLE	WA	98104	KING	USA	Kidney Diseases, Urology and Hematology Research	000	11	3/21/2002	EXTENSION WITH OR WITHOUT FUNDS	$708,347
														Subtotal = $708,347

Grand Total All Awards = $13,209,820

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Function of human & mouse Beta-globin locus control regions

Award Number: R37DK044746

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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