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Reprogramming of the Trypanosoma brucei epigenome during human infection: opportu

Award Number: U01HG007465
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/25/2013
PERIOD OF PERFORMANCE END DATE: 07/31/2017

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Reprogramming of the Trypanosoma brucei epigenome during human infection: opportu - DESCRIPTION (provided by applicant): This proposal aims to study the reprogramming of the Trypanosoma brucei epigenome that accompanies movement of this trypanosome from the insect to the human host. T. brucei causes African sleeping sickness or trypanosomiasis, and occurs in extensive parts of sub-Saharan Africa. Hundreds of thousands of individuals suffer from trypanosomiasis. The epigenome of an organism represents heritable information that is encoded outside of the nucleotide sequence of its genome, and includes nucleosome positions, histone isotypes, reversible histone modifications, and DNA modifications. The epigenome is an essential regulatory interface to the control of DNA function, and epigenetic misregulation is responsible for many serious human diseased states. The epigenome thus represents a potent therapeutic target, and several compounds that interfere with proteins that recognize or that confer specific histone modifications have either received FDA approval or are undergoing clinical trials. These compounds hold tremendous promise for the treatment of diseases such as cutaneous T-cell lymphoma or multiple linked leukemia, the prevalent leukemia in human infants. The genome-wide mapping of nucleosome positions and the elucidation of the modification types and positions of the histone H3 tail in T. brucei are planned in this proposal. Nucleosome positions will be mapped by paired end sequencing of 147 bp nucleosome fragments isolated from procyclic fly form (PF) and from human blood form (BF) cultures. The sequenced fragments will be aligned to the T. brucei genome, and the nucleosome positions mapped relative to the polycistronic transcription units and silent genomic loci. It was suggested that in the absence of a defined transcription start sequence in T. brucei, the correct positioning of an RNA polymerase at the start of a polycistronic unit was conferred by local chromatin structure and histone modifications. It is therefore expected that nucleosome positions and histone modifications will play a major role in understanding epigenetic control of transcription. Intriguingly, the T. brucei H3 tail lacks K9, generally associated with transcriptional repression n the tri-methylated state. In this study the type and position of modifications of the H3 tail, as wll as the genome-wide distribution of select modifications, will be determined by LC-MS/MS and by ChIP-seq. Particular attention will be paid to modifications associated with silent genomic loci and with silent Expression Sites (ES). A single Variable Surface Glycoprotein (VSG) is mono-allelically expressed from one of 15 ESs. Switching of the ES and the expressed VSG allows continual evasion of the human immune system. It is likely that insight into the epigenomic reprogramming of T. brucei associated with human infection will identify novel epigenetic targets for future drug development.


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: 2020 ( Subtotal = -$2,770 )
2020	2016	UNIVERSITEIT STELLENBOSCH	ADMINISTRATION BUILDING B, VICTORIA STREET	STELLENBOSCH		7600		ZAF	Trans-NIH Research Support	000	5	2/25/2020	NON-COMPETING CONTINUATION	-$2,770
														Subtotal = -$2,770

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2016	UNIVERSITEIT STELLENBOSCH	VICTORIA STREET	STELLENBOSCH		7600		ZAF	Trans-NIH Research Support	004	5	12/20/2018	NON-COMPETING CONTINUATION	$0
2019	2016	UNIVERSITEIT STELLENBOSCH	VICTORIA STREET	STELLENBOSCH		7600		ZAF	Trans-NIH Research Support	000	5	10/29/2018	NON-COMPETING CONTINUATION	-$272,324
2019	2016	UNIVERSITEIT STELLENBOSCH	VICTORIA STREET	STELLENBOSCH		7600		ZAF	Trans-NIH Research Support	003	5	11/28/2018	NON-COMPETING CONTINUATION	$272,324
2019	2015	UNIVERSITEIT STELLENBOSCH	VICTORIA STREET	STELLENBOSCH		7600		ZAF	Trans-NIH Research Support	001	4	10/29/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$135,329
2019	2015	UNIVERSITEIT STELLENBOSCH	VICTORIA STREET	STELLENBOSCH		7600		ZAF	Trans-NIH Research Support	002	4	11/28/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$135,329
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2015	UNIVERSITY OF THE FREE STATE	205 NELSON MANDELA DRIVE	BLOEMFONTEIN		9301		ZAF	Trans-NIH Research Support	001	3	2/9/2018	NON-COMPETING CONTINUATION	-$34,792
2018	2015	UNIVERSITEIT STELLENBOSCH	VICTORIA STREET	STELLENBOSCH		7600		ZAF	Trans-NIH Research Support	002	4	2/9/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$302,942
2018	2014	UNIVERSITY OF THE FREE STATE	205 NELSON MANDELA DRIVE	BLOEMFONTEIN		9301		ZAF	Trans-NIH Research Support	000	2	2/9/2018	NON-COMPETING CONTINUATION	-$268,150
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $272,324 )
2016	2016	STELLENBOSCH UNIVERSITY	CLINICAL BUILDING	TYGERGBERG				ZAF	Trans-NIH Research Support	002	5	7/30/2016	NON-COMPETING CONTINUATION	$272,324
2016	2015	UNIVERSITY OF THE FREE STATE	205 NELSON MANDELA DRIVE	BLOEMFONTEIN				ZAF	Trans-NIH Research Support	001	3	1/21/2016	NON-COMPETING CONTINUATION	-$237,532
2016	2015	STELLENBOSCH UNIVERSITY	CLINICAL BUILDING	TYGERGBERG				ZAF	Trans-NIH Research Support	000	4	1/21/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$237,532
														Subtotal = $272,324

Issue Date FY: 2015 ( Subtotal = $272,324 )
2015	2015	UNIVERSITY OF THE FREE STATE	205 NELSON MANDELA DRIVE	BLOEMFONTEIN				ZAF	Trans-NIH Research Support	000	3	9/3/2015	NON-COMPETING CONTINUATION	$272,324
														Subtotal = $272,324

Issue Date FY: 2014 ( Subtotal = $272,324 )
2014	2014	UNIVERSITY OF THE FREE STATE	205 NELSON MANDELA DRIVE	BLOEMFONTEIN				ZAF	Trans-NIH Research Support	000	2	7/31/2014	NON-COMPETING CONTINUATION	$272,324
														Subtotal = $272,324

Issue Date FY: 2013 ( Subtotal = $256,673 )
2013	2013	UNIVERSITY OF THE FREE STATE	205 NELSON MANDELA DRIVE	BLOEMFONTEIN				ZAF	Trans-NIH Research Support	000	1	9/24/2013	NEW	$256,673
														Subtotal = $256,673

Grand Total All Awards = $1,070,875

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Reprogramming of the Trypanosoma brucei epigenome during human infection: opportu

Award Number: U01HG007465

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/25/2013

PERIOD OF PERFORMANCE END DATE: 07/31/2017

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