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William Fairbrother

Assistant Professor of Biology:
Molecular Biology, Cell Biology, & Biochemistry
Phone: +1 401 863 6215
Phone 2: +1 401 863 6215
William_Fairbrother@brown.edu

My lab uses a combination of computational biology and high throughput genomics techniques to identify functional elements in the genome. We seek to understand recognition events important in gene expression (i.e transcription and RNA splicing). Specific projects include 1) understanding how particular arrangements of sequence elements are read by the splicing machinery, 2) identifying mutations/polymorphisms that disrupt splicing in the human population and 3) Defining combinatorial interactions between transcription factors (mostly Oct and Forkhead factors) that help maintain the pluripotent state of embryonic stem cells (ES cells).

Biography

I majored in chemistry at Oberlin College then worked briefly as a freelance journalist before starting graduate school at Columbia University in the Department of Biological Sciences. My postdoctoral research at MIT was performed in Phil Sharp's Lab with Chris Burge as a joint postdoc advisor. Since coming to Brown I have focused on using high throughput and computational methods to define elements important in gene expression. I am married to Dr Andrea Arena (Asst. Prof, Department of Family Medicine) and we have two wonderful boys!

Interests

Fairbrother on Pubmed
I believe that large scale computational analysis in conjunction with functional assays will continue to be an effective way to answer questions about gene expression. Below, I have included a more detailed description of directions we are taking.

RNA SPLICING Alternative splicing plays a major role in creating the complexity and diversity observed in higher eukaryotic proteomes. The goal of the splicing group in the lab is to map regulatory elements around alternatively spliced exons. Unlike location studies, which map all the genomic targets of a particular driver, the focus here is on creating, within limited regions of the genome, complete high-resolution maps of targets for all the relevant drivers. The ultimate goal is to define modules (i.e. particular arrangements of cis-elements) that regulate splice site selection. With RNA, protein binding events can be further modulated by secondary structure. We have mapped binding sites for the U1snRNP the SR protein, SF2/ASF, and for the hnRNP protein, PTB, around 4000 alternatively spliced exons. In the PTB paper we demonstrate how features of RNA structure modulate protein accessibility. The lab has made a video that illustrates how this techniques works. Comparing these mappings shows very little overlap between the repressor PTB and the activator ASF - perhaps reflecting their antagonistic function. Protein interactome maps indicate that PTB associates with about 20 other RNA binding proteins possibly creating RNPs with their own distinct specificity and function. Repeating the PTB binding assays after perturbing the levels of these interacting protein should identify scenarios of combinatorial binding or competition.

HUMAN GENETICS One of the most fundamental goals of genetics is to connect variations in genomic sequence to a phenotype or trait. In the context of human disease, an analysis of hereditary disease alleles illustrate the types of variations that have been associated with disease. Conservative estimates list splicing defects as responsible for about 15% of all diseases. In reality, researchers have found that many mutations classified as "missense" are also exacerbated by splicing defects. In addition to disease alleles, there is the more subtle class of disease causing variations that have been identified by genome wide association studies (GWAs). GWAs return regions that are associated with disease. The causal variant is presumed to be amongst the several hundred polymorphisms that are in linkage disequilibrium with the associated SNP. Our lab seeks to predict which disease allele and which associated SNP causes a splicing defect. If the causal variant is known there is an emerging class of oligo therapies that can be used therapeutically to reverse splicing defects (see example).


STEM CELLS As part of our efforts to understand the regulatory circuitry of the core set of promoters that are important in maintaining pluripotency in stem cells, we have developed and published a high throughput method to screen large genomic regions for DNA protein complexes. This pilot approach for developing a high throughput, high-resolution nucleic acid binding assay has been further developed so we are now studying binding events in complex extract rather than binding with purified protein. Here we find several interesting features of the transcriptional circuitry that may be important to understanding stem cells and stem cell reprogramming events. We find pervasive competiton between Oct4 and FoxO1 for genomic targets upstream of genes that maintain "stemness". We find find that the paralog Oct1 modulates Oct4 specificity in ES cells and we demonstrate that features learned from the high throughput in vitro binding assay can be used to successsfully predict in vivo binding events. Our future directions will be to extend these findings on a genomic scale in ES cells and to complete the characterization of the pluripotency transcriptional control network.

Degrees

PhD

Awards

CCMB Scholarship Innovator Award 2007

Richard Salomon Award, "Discovering Combinatorial Codes in Splicing" (2005-2006)

Informatics Postdoctoral Fellowship, PhRMA Foundation (2003-2005)

James Howard McGregor Teaching Award, Columbia University (2000)

BP Research Experience Fellowship, Oberlin College (Summer 1989)

Institution

Columbia University

Affiliations

International Society for Computational Biology

Teaching

Genetics Bio47
Independant Research Bio 195/196
Bio 2200 Advanced Topics in Molecular Biology and Biochemistry (co-taught with Rebecca Page)

Funded Research

Arthur Salomon Award (December 2005)


FEDERAL FUNDING
1R21HG004524-01A1 (Fairbrother, PI) 04/26/2010-01/31/2012
NIH/NHGRI $275,000
Role: Principal Investigator
Discovering and Validating Functional Elements in the Genome
This is a technology development grant that describes a high throughput nucleic acid protein interaction assay. The major goals are optimizing the experimental assay/microarray detection and developing a computational suite of tools to analyzing binding.

NSF 1020552 (Fairbrother, PI) 08/01/10-07/31/12
NSF/MCB- Genes and Genome Systems $218,426.00
Role: Principal Investigator
CIS-regulatory Circuitry of Polypyrimidine Binding Proteins

1R01GM095612-01 "A Discovery Tool for Variations that Affect Splicing", $1,250,000, 12/01/2010 - 11/30/2015, NIH/NIGM,
The goal of this grant is to discover cases of allelic differences in RNA protein interactions and function.

Web Links

Curriculum Vitae

Download William Fairbrother's Curriculum Vitae in PDF Format


William Fairbrother

Read William Fairbrother's full Faculty Research Profile.

 

 

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