Petko Petkov, Ph.D.

Senior Research Scientist

Investigating genetics/mechanisms of recombination and role of PRDM9.

My research interests involve two scientific themes: 1) meiotic recombination and genes that affect recombination positioning and activity; and 2) chromatin organization and its role in differentiation and gene expression. Our work in meiotic recombination resulted in the discovery of the major recombination positioning gene in mice and humans, Prdm9. PRDM9 is a histone methyltransferase that binds DNA via its zinc finger domain and creates open chromatin structure, thereby setting the stage for double-strand break (DSB) initiation and subsequent recombination events. We developed Affinity-seq, an in vitro approach for detecting all DNA-binding sites of PRDM9 genome-wide, which we are now applying to other DNA-binding proteins with the goal of developing improved prediction programs for motifs and binding sites. We also found that PRDM9 functions are dependent on its interaction with several other proteins, of which we have identified EWSR1, EHMT2, and CDYL, and that its methyltransferase activity at recombination hotspots is not only dependent on its DNA-binding specificity, but is also affected by local chromatin structure and is subject to trans regulation by distant genes.

Recently, I turned my attention to the role of chromatin structure on hepatocyte development and function. We found unusually diverse distributions of chromatin marks in hepatocytes of different strains, and determined that responses of these chromatin-mark distributions to corticosteroid treatment involved the same pathways across strains but not necessarily the same genes. We specifically addressed the influence of trans-acting factors on chromatin-activating marks in hepatocytes of two mouse lines, C57BL/6J and DBA/2J, using their F1 hybrids and derivative recombinant inbred lines as tools for detecting trans-acting regulators. We are now extending these studies to determine the genes regulating the positioning of open and closed chromatin in hepatocytes of Diversity Outbred (DO) mice, an enormously diverse mouse population derived from eight founder strains, and how they affect gene expression.

My work on recombination hotspots, PRDM9, initiation of meiotic recombination, and the role of chromatin structure and protein interactors has resulted in over thirty publications to date in journals including Science, PLOS Biology, PLOS Genetics, Genome Biology, Current Biology, Trends in Genetics, Nature Reviews Genetics, Epigenetics and Chromatin, Genetics and Genome Research.

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Grants, honors and accomplishments

Ongoing Research Support 

5 P50 GM076468-07 Churchill (PI)
7/15/11-6/30/16
NIH/NIGMS
Center for Genome Dynamics - Project B: Systems Genetics of Meiotic Recombination
The goal of this project is to identify epistatic genes that interact in networks to control the location and activity of recombination hotspots. Role: Project Leader 

2 R01 GM078452-06A1 Petkov (PI)
8/1/12-4/30/16
NIH/NIGMS
Sex-Specific Regulation of Meiotic Recombination Hotspots
The goal of this project is to determine the factors regulating sex specificity of meiotic recombination, both in its regional distribution along the chromosomes and the activity of sex-specific recombination hotspots. Role: Principal Investigator 

TJL-CCSG-Pilot-PMP01 Petkov (PI)
12/01/12-10/30/13
The Jackson Laboratory Cancer Center
The Jackson Laboratory Cancer Center, 2012-2013 Pilot Feasibility Studies - Does PDRM9 Play a Role in Cancer?
The goal of this project is to determine whether the expression of Prdm9 influence the incidence of tumor formation and progression in Apc+/- mice. Role: Principal Investigator 

6 TJL DIF FY14 GWC Collab Carter (PI) 
05/01/14 - 04/30/16
The Jackson Laboratory Director’s Innovation Fund Genetics of Molecular Epigenetics
The goal of this project is to understand the consequences of genetic variation on genomewide transcript regulation Role: Joint PI 

Completed Research Support 

5 R01 GM078452-05 Petkov (PI)
3/1/07-7/31/12
NIH/NIGMS
Chromosome-wide Mapping of Recombinational Activity
The goal of this project is to achieve understanding of the principles that determine the existence and activity of recombinational hot spots across the genome. Role: Principal Investigator 

3 R01 GM083408-02S1Z Paigen (PI)
8/17/09-7/31/11
NIH/NIGMS
Transacting Genes Regulating Recombination Hotspot Activities - ARRA Administrative Supplement
The aim of this project is to search for genes suppressing and modulating recombination activity Role: Co-Investigator 

5 P50 GM076468-05 Churchill (PI)
4/1/06-7/14/11
NIH/NIGMS
Genome Dynamics: Evolution, Organization and Function - Project 5: Chromosome-wide Mapping of Recombinational Activity
The goal of this project is to create high-resolution genetic maps of Chr 11 in six mouse crosses and study how genetic background, sex and imprinting affect hotspot positioning and usage. This study will provide the necessary information to start a comprehensive mapping of genes regulating recombination activity. Role: Project Leader 

5 P50 GM076468-05 Churchill (PI)
4/1/06-7/14/11
NIH/NIGMS
Genome Dynamics: Evolution, Organization and Function - Core 3: Molecular Biology
The main task of this core is to provide high-quality DNA and RNA samples for Projects 1, 3 and 5, and to perform expression studies using Affymetrix microarrays and real-time PCR.. Role: Core Leader 

2 P40 RR016049-06A1 Donahue (PI)
9/1/06-6/30/11
NIH/NCRR
Special Mouse Strains Resource
The major goal of this project is to maintain, characterize and distribute recombinant inbred and consomic strains of mice. Role: Research Scientist 

5 R21 AR055181-02 Petkov (PI)
7/1/08-5/31/11
NIH/NIAMS
Search for Genes Involved in Arthritis Pathogenesis
The specific aims of this project are: (1) Map the region on chromosome 6 responsible for arthritis resistance using a backcross between B6-Chr6PWD and B6, and select candidate genes. (2) Evaluate arthritis susceptibility and clinical parameters of arthritis development using the entire set (n=28) of ChrNPWD consomics and the serum-transfer model of arthritis. 7 Role: Principal Investigator 

5 R01 GM078643-03 Paigen (PI)
1/1/06-12/31/10
NIH/NIGMS
Genomic Organization of Recombination Hot Spots
The major goal of this grant is obtain a detailed map at one Kb resolution of all recombinational hotspots, including their sex and haplotype specificity, for five different five Mb regions chosen for their particular biological interest on separate chromosomes using 6000 meioses. Role: Co-Investigator 

AG-SS-1631-06 Paigen (PI)
10/2/06-10/1/10
Ellison Medical Foundation New Genetic Strategies in the Study of Aging
The goal of this project is the development of new genetic strategies in the study of human aging using RNAi directed mutagenesis in somatic cell cultures to identify previously unknown genes participating in the aging process. Role: Co-Principal Investigator