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Combinatorial control of Met4-activated transcription

Award Number: R15GM086847
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/08/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2016

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Combinatorial control of Met4-activated transcription - DESCRIPTION (provided by applicant): Modulation of gene expression is achieved in part by a conserved regulatory mechanism called combinatorial control, in which permutations among a fixed set of transcription factors at a promoter allow different transcriptional responses. One aspect of combinatorial control is how families of transcription factors that bind the same promoter motif behave differently to allow distinct expression outcomes. We study this issue in a well characterized yeast system that modulates expression of sulfur metabolism genes in response to varying environmental cues. Transcription of these genes depends on one activator called Met4. Since Met4 lacks intrinsic DNA binding ability, Met4 relies on interactions with DNA-binding "cofactors" (transcription factors that lack intrinsic activation ability) to target Met4 to specific promoters. There are two classes of DNA-binding cofactors for Met4 with each class binding a distinct DNA motif. One class consists of the basic helix-loop-helix protein Cbf1; the other class consists of two similar and semi-redundant zinc finger proteins: Met31 and Met32. While we have uncovered that Cbf1 is required for a subset of Met4 target genes to be expressed, all Met4 target gene expression is eliminated upon removal of both Met31 and Met32 [1]. The aim of this proposal is to determine the individual roles of Met31 and Met32 in mediating Met4-activated transcription. Using a genome-wide approach, we will identify targets in terms of promoter binding and transcriptional response and calculate DNA consensus motifs that are specific for Met31 and for Met32. We will also examine how loss of either Met31 or Met32 alters the combinatorial components within the Met4 transcriptional system. When comparing the above data with target promoter composition, we hope to provide more detailed insights into how transcription factor families allow a broad range of transcriptional responses for their targets. The general mechanisms uncovered from this study are likely to be conserved in higher eukaryotes, which contain much larger, more complex, transcription factor families that are intractable to these kinds of analyses. PUBLIC HEALTH RELEVANCE: Transcription factor families, whose members bind the same promoter motif, are found throughout eukaryotic gene regulation systems. These families allow a broad range of transcriptional responses for their targets. By manipulating a well-characterized yeast system, we will examine how a simple two-member transcription factor family orchestrates gene expression of its multiple targets in response to different signaling cues.


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: 2015 ( Subtotal = $0 )
2015	2011	UNIVERSITY OF WISCONSIN PARKSIDE	900 WOOD ROAD BOX 2000	KENOSHA	WI	53141	KENOSHA	USA	Biomedical Research and Research Training	000	1	6/19/2015	NEW	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2011	UNIVERSITY OF WISCONSIN PARKSIDE	900 WOOD ROAD BOX 2000	KENOSHA	WI	53144	KENOSHA	USA	Biomedical Research and Research Training	000	1	1/6/2012	NEW	-$289,203
2012	2011	UNIVERSITY OF WISCONSIN PARKSIDE	900 WOOD ROAD BOX 2000	KENOSHA	WI	53144	KENOSHA	USA	Biomedical Research and Research Training	001	1	1/10/2012	NEW	$289,203
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $289,203 )
2011	2011	BOARD OF REGENTS OF UW SYSTEM- EXTENSION	432 N LAKE STREET, 104 EXT BLD	MADISON	WI	53706	DANE	USA	Biomedical Research and Research Training	000	1	6/24/2011	NEW	$289,203
														Subtotal = $289,203

Grand Total All Awards = $289,203

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Combinatorial control of Met4-activated transcription

Award Number: R15GM086847

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/08/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2016

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