This federal Project Grant award from the National Institute of General Medical Sciences (NIGMS), under the Biomedical Research and Research Training program (CFDA 93.859), provides $611,728 to the University of California, Berkeley to conduct research on the molecular mechanisms by which the transcription factor Dorsal controls gene expression dynamics during early embryonic development in Drosophila melanogaster. The key objectives are to: (1) determine how Dorsal modulates transcriptional...
This $588,426 Project Grant award, provided by the National Institutes of Health (NIH) Office of the Director under the Trans-NIH Research Support program (CFDA 93.310), aims to investigate how transcription factors efficiently locate and bind to specific DNA binding sites within the crowded nucleus of living cells. The project will employ advanced microscopy techniques to precisely track the 3D diffusion, DNA interactions, and target site discrimination of transcription factors involved in...
This $409,896 Project Grant awarded by the National Institute of General Medical Sciences (NIGMS) under the Biomedical Research and Research Training program (CFDA 93.859) supports the development of novel statistical methods and analyses to leverage functional genomics data, in conjunction with genome-wide association study (GWAS) data, to identify and characterize the functional effects of genetic variants and their roles in diseases. The key objectives are: (1) to establish a powerful...
This Project Grant award from the National Institutes of Health (NIH) Office of the Director under the Trans-NIH Research Support program (CFDA 93.310) provides $1,507,500.00 to Yale University to conduct research on the regulatory mechanisms by which the genome encodes non-genetic heterogeneity in cell systems. The project aims to identify transcription factor pairs that drive transcriptional heterogeneity, determine heritable memory loci capable of transmitting non-genetic heterogeneity across...
The National Institute of General Medical Sciences (NIGMS), under the Biomedical Research and Research Training (CFDA 93.859) program, awarded a $445,000 Project Grant to The Children's Hospital of Philadelphia (CHOP) on June 1, 2025. The goal of this 5-year project is to harness the power of long-read transcriptomics to elucidate transcriptome complexity and advance genomic medicine. Key objectives include: 1) developing technologies to delineate haplotype-resolved, full-length transcriptomes...
This federal Project Grant award of $651,596 from the National Institute of General Medical Sciences (NIGMS) Biomedical Research and Research Training Program (CFDA 93.859) supports research by the Cold Spring Harbor Laboratory (CSHL) to study the molecular mechanisms that coordinate gene expression, cell fate determination, and tissue growth during development. The key research objectives are to: 1) Determine the molecular structures and dynamics of three transcriptional complexes that regulate...
This federal Project Grant award of $142,065 from the National Human Genome Research Institute (CFDA 93.172 - Human Genome Research) supports the development of computational frameworks to model the impact of external signals on a cell's internal transcription factor activity. The key products and services to be delivered under this award include: Computational methods to more accurately deconvolve cell type fractions and gene expression from bulk RNA-seq and spatial transcriptomics data. A...
The National Institute of General Medical Sciences (NIGMS) awarded a $415,252 Project Grant under the Biomedical Research and Research Training (CFDA 93.859) federal grant program to The Regents of the University of California, doing business as the University of California, Berkeley (UC Berkeley). The grant, effective July 1, 2025 through June 30, 2030, will support research to develop a predictive understanding of transcriptional regulation in early embryonic development. Key objectives...
This Project Grant award of $272,914 from the National Science Foundation's (NSF) Division of Molecular and Cellular Biosciences (CFDA 47.074 Biological Sciences) supports research to understand how cells interpret and respond to stress signals. The primary research objectives are to examine: 1) post-transcriptional regulation of genes through mRNA stability, and 2) combinatorial regulation of genes by multiple transcription factors. The research will use experimental techniques like metabolic...
This $240,000 Project Grant award from the National Science Foundation (NSF) Biological Sciences program (CFDA 47.074) funds a postdoctoral research fellowship to investigate the role of genome organization on de novo gene origination. The research aims to test a new theoretical model explaining the process of new gene evolution, by examining how the genome's structural features influence the birth of genes that arise from non-coding regions. The key components of the research include: 1)...
AN INTEGRATED TOOLKIT FOR REAL-TIME ANALYSIS OF COUPLED NASCENT TRANSCRIPTION - PROJECT SUMMARY PROPER REGULATION OF GENE EXPRESSION IS REQUIRED FOR CELLULAR FUNCTION. CONVERSELY, DYSREGULATION OF GENE EXPRESSION IS A MAJOR CAUSE OF DISEASE. FURTHERMORE, EXPRESSION OF TWO GENES IS FREQUENTLY COUPLED. COUPLED EXPRESSION IS EXPECTED IF TWO GENES RESPOND TO THE SAME SIGNAL OR ARE EXPRESSED FROM A BIDIRECTIONAL PROMOTER (BDP). ABOUT ONE IN TEN HUMAN GENES ARE CONTROLLED BY A BDP, DEFINED AS TWO GENES WITH LESS THAN 1 KILOBASE BETWEEN THEIR TRANSCRIPTION START SITES. HOWEVER, COUPLED EXPRESSION IN GENERAL AND BDPS IN PARTICULAR REMAIN VERY POORLY UNDERSTOOD. THE PREMISE OF THIS PROPOSAL IS THAT OUR CURRENT LACK OF UNDERSTANDING OF COUPLED EXPRESSION IS DUE TO A LACK OF TOOLS. THE GOAL OF THIS PROPOSAL THEREFORE IS TO DEVELOP AN INTEGRATED EXPERIMENTAL AND COMPUTATIONAL TOOLKIT FOR REAL-TIME ANALYSIS OF COUPLED NASCENT TRANSCRIPTION. FOR EXAMPLE, WE CURRENTLY DO NOT UNDERSTAND IF TRANSCRIPTION OF TWO BDP-CONTROLLED GENES IS SYNERGISTIC, ANTAGONISTIC, OR INDEPENDENT IN QUANTITY AND IN TIME. MORE GENERALLY, UNDERSTANDING COUPLED EXPRESSION IN BOTH QUANTITY AND TIME REQUIRES REAL-TIME SINGLE-MOLECULE IMAGING OF NASCENT TRANSCRIPTION INTEGRATED WITH COMPUTATIONAL MODELING. HERE WE PROPOSE TO DEVELOP AN EXPERIMENTAL PLATFORM THAT ALLOWS DIRECT VISUALIZATION OF NASCENT RNA OF TWO GENES (AIM 1). SPECIFICALLY, WE WILL ADAPT RNA HAIRPIN SYSTEMS FROM BACTERIOPHAGE TO ALLOW REAL-TIME VISUALIZATION AND COUNTING OF SINGLE NASCENT RNAS IN LIVE CELLS. WE WILL EVALUATE MULTIPLE MICROSCOPE MODALITIES AND OPTIMIZE A MICROSCOPY PLATFORM FOR LONG-TERM GENTLE LIVE-CELL IMAGING AT HIGH SPATIOTEMPORAL RESOLUTION. NEXT, WE WILL DEVELOP COMPUTATIONAL METHODS FOR QUANTIFICATION OF NASCENT BDP TRANSCRIPTION IMAGING DATA (AIM 2). WE WILL ALSO DEVELOP BAYESIAN INFERENCE METHODS FOR INFERENCE OF TWO-GENE COUPLED NASCENT TRANSCRIPTION DATA, AND IDENTIFY THE MINIMAL MATHEMATICAL MODELS REQUIRED TO UNDERSTAND BDP TRANSCRIPTION. NEXT, WE WILL APPLY THESE NEW EXPERIMENTAL AND COMPUTATIONAL TOOLS FOR AN INITIAL EXPLORATION OF BDPS (AIM 3). SPECIFICALLY, WE WILL TAKE A TWO-PRONGED APPROACH EXPLORING MULTIPLE BDPS AT A SAFE-HARBOR LOCUS AS WELL AS DEDICATED STUDIES OF THE ENDOGENOUS NIPBL BDP. THIS WILL SERVE AS PROOF-OF-CONCEPT FOR OUR INTEGRATED TOOLKIT. IN SUMMARY, WE PROPOSE TO ESTABLISH AN INTEGRATED EXPERIMENTAL AND COMPUTATIONAL TOOLKIT FOR REAL-TIME ANALYSIS OF COUPLED NASCENT TRANSCRIPTION. WE WILL DEVOTE SIGNIFICANT EFFORTS TO DISSEMINATE THE EXPERIMENTAL AND COMPUTATIONAL TOOLS AND ANTICIPATE THIS BEING USEFUL BEYOND BDP STUDIES. WE ANTICIPATE THIS TOOLKIT WILL ALLOW FUTURE MECHANISTIC STUDIES TO BETTER UNDERSTAND BDPS, WILL MAKE IT POSSIBLE TO ESTABLISH BDPS AS POWERFUL TOOLS FOR SYNTHETIC BIOLOGY, AND EMPOWER STUDIES OF COUPLED NASCENT TRANSCRIPTION BEYOND BDPS.