the pai lab

the kinetics of gene regulation

About Us

Welcome to the Pai Lab in the RNA Therapeutics Institute at the University of Massachusetts Medical School. We study the speed and efficiency at which RNA molecules are created and processed to ensure proper cellular functions.

Our lab combines high-dimensional computational analyses with state-of-the art genetic, molecular, and cellular genomics techniques to probe mechanisms of RNA maturation. We are looking for enthusiastic researchers interested in experimental and/or computational biology to JOIN US!

news

Apr18 Welcome to rotation students Eleni, Garhom, and Paul - looking forward to exploring exciting potential projects over the next couple months!

31418 First annual Pai Lab Pi Day Pie Party served as our lab warming. Thanks to our many colleagues for showing up to enjoy pi[e] with us! #paipipie

Jan18 Nida Javeed joins as our first lab member. Welcome Nida!

Jan18 The Pai Lab is officially open! Plenty of boxes to be unpacked and files to be moved!

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research

Distribution of mean splicing half-lives across bins of RIME (θ axis) and deciles of joint intron and exon lengths (r axis). While 60-70nt introns are spliced more efficiently, putative exon-defined introns are spliced faster than intron-defined introns in flies. [1]

Phenotypic variation in humans is driven by coordinated changes in gene regulation that allow a continuum of gene expression levels to arise from the same genome sequence. Recent studies have provided unprecedented insight into how individual molecular mechanisms regulate changes in mRNA levels and revealed that substantial transcriptome diversity arises from the differential processing of nascent RNAs. Many studies of gene expression focus on characterizing steady-state mRNA levels, even though living systems are inherently dynamic. Thus, a key unanswered question underlying functional genomics is: how do the dynamics of individual molecular processes combine to influence the cellular transcriptome?

Our lab seeks to answer this question by investigating how the kinetics of disparate steps of gene regulation are regulated synergistically to influence steady-state mRNA levels. In particular, we focus on characterizing the speed and efficiency of essential steps in the life-cycle of an RNA molecule - transcriptional elongation, pre-mRNA splicing, and cleavage and polyadenylation - to profile how these steps are coordinated to create mature mRNA molecules. We do this using a experimental techniques to isolate newly created nascent RNA, followed by high-throughput sequencing and computational and mathematical modeling approaches to simultaneously measure the rates of each RNA processing step along a gene body. Genome-wide measurements provide us with the ability to learn about the cellular logic and regulatory grammer involved in efficient RNA processing. We have previously used these methods to study the rates of mRNA splicing in flies, which provided insights about genomic features that influence variability in rates and mechanistic choices made during intron recognition for mRNA splicing.

[1] (view) The kinetics of pre-mRNA splicing in the Drosophila genome and the influence of gene architecture. Pai AA, Henriques T, McCue K, Burkholder A, Adelman K, Burge CB. eLife 2017, 6, e32537

Distribution of deltaPSI values for each RNA processing category after infection with either Listeria or Salmonella bacteria. Negative values represent less inclusion, while positive values represent more inclusion, as defined by the schematic exon representations. There are striking global shifts towards increased inclusion of skipped exons and the shortening of 3' UTRs following infection with either bacteria. [1]

Changes in gene regulation have long been known to play an important role in any cellular response, with many previous studies extensively characterizing transcriptional response pathways. However, post-transcriptional mechanisms, especially those involved in mRNA process and alternative splicing, remain understudied despite gaining prominence as crucial regulators of cellular defense systems.

In collaboration with Luis Barreiro's lab at the University of Montreal, we have been studying the dynamics of transcriptional and post-transcriptional regulation in response to infection by naturally occuring pathogens (Listeria monocytogenes and Salmonella typhimeurium), with a particular focus on investigating the role of mRNA processing during cellular reponses. In an initial study[1], we discovered thousands of changes in isoform usage following infection. Immune response was characterized by specific changes in mRNA splicing and polyadenylation site choice, with global shifts towards increased inclusion of cassette exons and a widespread usage of upstream polyadenylation sites in genes upregulated after infection. Favoring shorter 3' UTRs after infection likely allows immune-relevant transcripts to escape repression by miRNAs activated in response to infection. We are continuing work on the mechanisms of mRNA processing dynamics during the immune response and mapping genetic loci that influence inter-individual differences in immune response through mRNA processing pathways.

For a broader perspective on the dynamics of mRNA processing, we investigated mRNA processing changes across a panel of cellular responses to environmental and drug stimulii in collaboration with the labs of Francesca Luca and Roger Pique-Regi at Wayne State University[2]. Simular to immune response, we see clear signatures of directed shifts in particularly RNA processing mechanisms, in a stimulus-dependent manner. Combined with functional genomic data and knowledge of regulated pathways, we are able to identify trans-acting factors that influence RNA isoform usage, particularly for alternative transcription start sites. Overall, our work clearly demonstrates the ubiquity of post-transcriptional mRNA changes related to gene expression response to the environment, including for key functions like the innate immune response and drug response.

[1] (view) Widespread Shortening of 3' Untranslated Regions and Increased Exon Inclusion Are Evolutionarily Conserved Features of Innate Immune Responses to Infection. Pai AA, Baharian G, Sabourin A, Brinkworth JF, Nédélec Y, Foley JW, Grenier J, Siddle KJ, Dumaine A, Yotova V, Johnson ZP, Lanford RE, Burge CB, Barreiro LB. PLOS Genetics 2016, 12(9), e1006338

[2] (view) Environmental perturbations lead to extensive directional shifts in RNA processing. Richards AL, Watza D, Findley A, Alazizi A, Wen X, Pai AA, Pique-Regi R, Luca F. PLOS Genetics 2017, 13(10), e1006995

people

Athma was born in Stamford, CT, once called the "Research City" due to it's bustling innovation-driven economy. She was fascinated by science at an early age, inspired by her father's demonstrations of bright chemiluminescent displays and working her way through all the science fiction books in the local library. In high school, she discovered genetics by reading Matt Ridley's Genome: An Autobiography of a Species in 23 Chapters.

At the University of Pennsylvania, Athma managed to simultaneously pursue her interests in genetics, chemistry, and evolution by majoring in Biochemistry and Anthropology and doing research in an anthropological genetics lab studying the genetic signatures of human migration. Continuing in this vein, she pursued graduate work in human and comparative genomics in the Department of Human Genetics at the University of Chicago. Working with Yoav Gilad and collaborating closely with Jonathan Pritchard's group, Athma applied both experimental and computational approaches to understanding how gene regulatory variation in humans and closely related primates established their gene expression signatures. One primary focus of her work was to map molecular quantitative trait loci (QTLs) in humans for many transcriptional regulatory mechanisms.

To gain more experience in understanding the molecular details of gene regulatory mechanisms, Athma did her postdoctoral research as a Jane Coffin Childs Fellow at MIT working with Christopher Burge. She focused on understanding the changes in mRNA splicing and RNA processing mechanisms after immune response and developing methods to measure the dyanmics of such processes. Her transition to an RNA systems geneticist complete, Athma assumed her current position as an Assistant Professor in the RNA Therapeutics Institute at UMMS in January 2018. Her research focuses on developing and applying methods to study the kinetics of RNA processing and understanding how various steps in RNA maturation are coordinated through the lifecycle of an RNA molecule. In her spare time, Athma enjoys traveling, racquet sports, experimenting with molecular gastronomy, and finding the best ice cream in New England.

Nida Javeed
Research Associate
Athma Pai
PI
You?

Graduate Students: We are actively recruiting graduate students from the GSBS doctoral program at UMass Medical School in Worcester. Prospective students should apply directly to this program and current students are welcome to e-mail Athma to discuss rotation projects! Graduate students will have the chance to learn techniques spanning experimental genomics to computational biology and mathematical modeling with the goal of understanding fundamendal molecular mechanisms and their mis-regulation in human diseases.

Postdoctoral Scholars: We are currently looking for 1-2 enthusiastic and creative postdoctoral scholars. The ideal candidate will have experience in both experimental and computational genomics, but we welcome all applicants with an interest in expanding their skill-sets in RNA biology, genomics and computational biology. For more details, please see our advertisement and e-mail Athma with the necessary material.

Other positions: We encourage inquiries from undergraduate researchers from the New England area or visiting scientists from any discipline. Please email Athma to see whether there are any such opportunities available in the lab at the moment.

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publications

# Abstract Authors Title Journal Year

contact

The Pai Lab
RNA Therapeutics Institute
UMass Medical School
368 Plantation Street, AS5-2057
Worcester, MA 01605

wet-lab: AS5-2003/2004
dry-lab: AS5-2053/2055

athma.pai@umassmed.edu
Admin: Ann Powers (ann.powers@umassmed.edu)

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Athma Pai

athma.pai@umassmed.edu

B.A. University of Pennsylvania 2007
Ph.D. University of Chicago 2012
Jane Coffin Childs Postdoctoral Fellow, MIT 2012-17
Google Scholar | PubMed

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Nida Javeed

nida.javeed@umassmed.edu

B.S. Microbiology, University of California, Davis 2012

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You?

We have open opportunies to join us! Please see details here.

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The Pai lab at UMass Medical School is seeking a postdoctoral candidate in the field of RNA biology and functional genomics with relevant experience in experimental and/or computational biology. Our research combines high-dimensional computational analyses with state-of-the-art genetic, molecular, and cellular genomic techniques to probe the molecular mechanisms of RNA maturation (including transcription, splicing and 3' end processing). We specifically focus on characterizing the kinetics of RNA processing steps to understand the overall speed and efficiency at which RNA molecules are created and processed to ensure proper cellular functions.

Ideal applicants will have a strong background in RNA biology, functional genomics, systems biology, or computational biology/bioinformatics. We desire a candidate with both experimental and computational skills, but encourage applications from scientists motivated to expand their skillset to include both approaches. Applicants must be self-motivated, creative, and able to work in a highly collaborative and interdisciplinary environment.

Responsibilities include:

Desired qualifications:

To apply, please e-mail the following to Athma Pai at athma.pai@umassmed.edu:

  1. Curriculum vitae, including complete list of publications and pre-prints.
  2. Contact information for three referees.
  3. Summary of your present research (1 page max).
  4. Outline of your future research interests (1 page max).

This position is in the RNA Therapeutics Institute at the University of Massachusetts Medical School in Worcester, MA. To learn more about the Pai lab, please visit our website. The RNA Therapeutics Institute is an exceptional training environment, with many interactive and highly collaborative research groups uniting researchers studying fundamental RNA mechanisms with the active development of RNA-based therapeutic strategies. The department has strong intellectual and proximity-based links with neighboring groups in Bioinformatics and Integrative Biology and the Program in Systems Biology at UMass Medical School, creating a stimulating interdisciplinary research environment with world-class expertise in many disciplines relevant for our work.

UMass Medical School is committed to being an equal opportunity and affirmative action employer and recognizes the power of a diverse community. We encourage applications from protected veterans, individuals with disabilities and those with varied experiences, perspectives and backgrounds to consider UMass Medical School as their employer of choice.

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