2020 Requests for Proposals
The investigators of Memorial Sloan Kettering Cancer Center have been invited to submit competitive research applications for support from the CER. The goal is to support highly creative and innovative research in epigenetics at MSKCC, and especially projects that have the potential to lead to significant scientific breakthroughs in epigenetics research.
Two types of research projects will be funded:
Pilot Project Grants (1 year support): These awards serve to provide seed money for pilot and feasibility studies, in which epigenetics is a main component, with the resulting data serving as a basis for grant applications to outside agencies.
Project Collaborative Grants (2 years support): These awards require the collaboration between at least two MSK laboratories. Successful proposals use multidisciplinary approaches to obtain mechanistic insights into the role of epigenetic regulation in cellular processes, cell proliferation, differentiation, development and cancer.
Awarded Pilot Projects
Dr. Maria Jasin
Impact of histone modifications on homologous recombination
Whole genome profiling of chromatin modifications under unperturbed conditions and upon genotoxic stress have implicated epigenetic marks as playing important roles in the DNA damage response and DNA repair pathway choice. Double-strand breaks (DSBs) are considered to be particularly destabilizing genomic lesions, since misrepair or lack of repair can lead to genetic loss, mutagenesis, and genome rearrangements associated with cell lethality and carcinogenesis. DSBs are repaired by two major pathways, homologous recombination (HR) and non-homologous end-joining (NHEJ). HR is considered to be a relatively precise pathway of DSB repair because it can restore the original sequence. This pilot project aims to examine the impact of particular histone marks on HR frequency and outcome, with a special interest in HR between chromosome homologs.
Dr. Alexandros Pertsinidis
Many developmentally regulated genes contain RNA Polymerase II paused at ~50 nucleotides downstream of the transcription start site. Rapid transcription induction of such genes is accomplished by the release of paused Pol II into productive elongation via the action of Super- Elongation Complexes (SECs). SEC components are also frequently mutated in human tumors; oncogene activation by mutant SECs is implicated in the pathogenesis of various types of cancer. This project aims at (1) developing new systems for visualizing mechanisms by which SEC is targeted and activated at single-gene loci upon transcription induction by external stimuli; (2) understanding the interplay between the activities of SEC, Pol II transcription factors and chromatin regulators, and the nanoscale nuclear organization at active transcription sites. Our goal is to elucidate gene control mechanisms by SEC, in normal physiology and their de-regulation by certain cancer-causing SEC mutations.
Awarded Collaborative Projects
Dr. Thomas Vierbuchen / Co-Investigator: Dr. Danwei Huangfu
Characterizing the role of canonical and non-canonical SWI/SNF complexes in lineage specification from pluripotent stem cells
Large scale efforts such as the MSKCC IMPACT study have analyzed 1000s of tumor samples to figure out which genes are recurrently altered in human tumors, providing long lists of genes that are thought to play a role in tumor development, and which could be potential new targets for cancer therapies. These studies revealed that components of the SWI/SNF complex, a protein machine that is involved in switching genes on and off during normal development, are among the most frequently mutated genes in human cancers. However, we don’t know enough about the normal functions of this complex to be able to develop effective new therapeutic approaches to modulate its function. We are developing new approaches to study this complex in cells to better understand how it switches genes on and off and how specific proteins that make up this complex contribute to these functions.
Dr. Yael David / Co-Investigator: Dr. Xiolan Zhao
Studies of Smc5/6 as a multi-functional chromatin regulator
Structural maintenance of chromosomes (SMC) complexes are critical regulators of chromatin structure and genome integrity. Of the three SMC complexes in eukaryotic cells, the Smc5/6 complex is the least understood and has the most diverse effects on chromatin. For example, Smc5/6 facilitates DNA replication and repair in healthy cells, but it also exhibits antagonistic effects on viral chromosomes, including that of the Hepatitis B Virus (HBV). By employing chromatin reconstitution and protein biochemistry methods, our labs will seek to determine how Smc5/6 recognizes and differentially regulates different chromatin species.
Dr. Dana Pe’er / Co-Investigator: Dr. Anna-Katerina Hadjantonakis
Epigenetic mechanisms of visceral organ development
The midgestational mammalian embryo undergoes a dramatic set of patterning events as the visceral organs form and begin to bud from the gut tube. We discovered that the epigenome at this stage is highly plastic and receptive to signals that trigger organ-specific programs. Our current work aims to unravel the spatiotemporal dynamics of the chromatin landscape underlying visceral organ formation, by combining gut dissection with single-cell assays that simultaneously measure chromatin accessibility and gene expression. We will develop an algorithmic toolbox that can overcome the extremely sparse and noisy nature of single-cell chromatin accessibility data and leverage the joint profiling of two data types to resolve open chromatin regions and infer upstream factor binding at high resolution and sensitivity. Moreover, we will develop approaches to integrate genomic data types and model cell-cell communication. Our tools will reveal important regulatory insights into mammalian organogenesis and serve as a general community resource for epigenomic analysis.