The common theme underlying the questions being addressed in this proposal is how gene expression is controlled by cis-regulatory modules (CRMs) and the transcription factors that they bind during animal development. Answers to this question are becoming increasingly important in the emerging era of Personalized Medicine, since we now have the ability to sequence thousands of genomes and to identify changes in DNA sequences that correlate with diseases ranging from epilepsy to obesity. However, when changes in DNA sequence map to the non-protein coding portion of the genome, we are nearly helpless in interpreting these changes. This project will help bridge this gap in our knowledge by establishing methods to assess how the Hox family of transcription factors function in vivo. In the next several years, one goal is to extend what has been learned about Hox transcription factor specificity to a more in vivo level, in particular, to break the sequence code that allows these TFs to select biologically relevant binding sites in vivo. A second major goal is to understand at a deeper level how multiple transcription factors and CRMs coordinate with each other to regulate genes in the right cells and at the correct developmental time. For this last set of experiments, the focus is on how the proximo-distal axis of the Drosophila leg is established during development.

Public Health Relevance

This work aims to understand how genomic regulatory information is interpreted and deployed by transcription factors during animal development, using a combination of state-of- the-art genetic, biochemical, and high-throughput genomic methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM118336-04
Application #
9705992
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Hoodbhoy, Tanya
Project Start
2016-05-03
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biochemistry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Rastogi, Chaitanya; Rube, H Tomas; Kribelbauer, Judith F et al. (2018) Accurate and sensitive quantification of protein-DNA binding affinity. Proc Natl Acad Sci U S A 115:E3692-E3701
Newcomb, Susan; Voutev, Roumen; Jory, Aurelie et al. (2018) cis-regulatory architecture of a short-range EGFR organizing center in the Drosophila melanogaster leg. PLoS Genet 14:e1007568
Rao, Satyanarayan; Chiu, Tsu-Pei; Kribelbauer, Judith F et al. (2018) Systematic prediction of DNA shape changes due to CpG methylation explains epigenetic effects on protein-DNA binding. Epigenetics Chromatin 11:6
Voutev, Roumen; Mann, Richard S (2018) Robust ?C31-Mediated Genome Engineering in Drosophila melanogaster Using Minimal attP/attB Phage Sites. G3 (Bethesda) 8:1399-1402
Zeiske, Tim; Baburajendran, Nithya; Kaczynska, Anna et al. (2018) Intrinsic DNA Shape Accounts for Affinity Differences between Hox-Cofactor Binding Sites. Cell Rep 24:2221-2230
Requena, David; Álvarez, Jose Andres; Gabilondo, Hugo et al. (2017) Origins and Specification of the Drosophila Wing. Curr Biol 27:3826-3836.e5
Kribelbauer, Judith F; Laptenko, Oleg; Chen, Siying et al. (2017) Quantitative Analysis of the DNA Methylation Sensitivity of Transcription Factor Complexes. Cell Rep 19:2383-2395
Voutev, Roumen; Mann, Richard S (2017) Bxb1 phage recombinase assists genome engineering in Drosophila melanogaster. Biotechniques 62:37-38
Chiu, Tsu-Pei; Rao, Satyanarayan; Mann, Richard S et al. (2017) Genome-wide prediction of minor-groove electrostatic potential enables biophysical modeling of protein-DNA binding. Nucleic Acids Res 45:12565-12576
Voutev, Roumen; Mann, Richard S (2016) Streamlined scanning for enhancer elements in Drosophila melanogaster. Biotechniques 60:141-4

Showing the most recent 10 out of 15 publications