People

Principal Investigator

Lab Members

Postdoctoral Researchers

There is substantial interest in the evolutionary forces that shaped developmental gene regulation in humans, rodents, and other mammals. Early embryos are patterned and specialized into different cell types by inductive signaling molecules and transcription factors. How these signaling pathways are integrated at transcriptional enhancers to specify embryonic cell fates in mammalian development is not well understood. We posit that in many cases, evolutionary divergence in gene expression patterns and embryonic cell fates are caused by alterations in enhancer sequences. We integrate functional genomics, computational data mining with mouse and human embryonic stem cell (ESC) models of early embryonic tissues to determine species-specific patterns of enhancer activity. Our studies will identify cases of enhancer sequence evolution that lead to regulatory innovations in developmental gene expression programs.

PhD Candidates

Trophoblast stem-cells are the first lineage commitment that the early embryo makes after fertilization and go on to become the placenta and extra-embryonic tissues of the fetus. Our collaborators have previously discovered a critical, maternally imprinted gene, Sfmbt2, which has seen to be required for the normal development of fetus by allowing the trophoblast stem-cells to divide indefinitely. My project aims to identify what cis-regulatory elements regulate Sfmbt2 and whether they are also responsible for its parent-of-origin expression. To understand its regulation, I employ CRISPR-Cas9 mediated deletions, gene expression using qPCR, Site-Directed Mutagenesis, enhancer reporter assays, and in vivo studies using genome edited mice.

Preterm labour is a global concern, lacking effective treatments due to the poorly understood molecular mechanisms underlying contractions in the uterine muscle tissue known as the myometrium. Gene regulation occurs via a complex interplay between transcriptional factors and regulatory regions that allow the uterus to transition from a quiescent to a contractile phenotype. My research project focuses on the role of transcriptional regulation in the myometrium to better understand the process of pregnancy and labour. For this, I commonly carry out experiments such as qPCR and those involving next generation sequencing techniques, namely ATAC-seq and ChIP-seq, on myometrium tissue.

Enhancers are DNA regulatory elements that control cell-type specific gene expression and are crucial for organism development. Despite their importance, we do not have a good understanding of how this function is encoded into the enhancer DNA sequence. My research focuses on using machine learning, along with comparative genomics and genome evolution to learn the enhancer sequence code.

Luis

SOX2 is a pluripotency-associated transcription factor that is often upregulated in multiple types of cancer, where it has been linked with increased tumourigenesis, metastasis, proliferation and poor patient outcome. My current goal is to identify (1) the epigenetic mechanisms that result in SOX2 upregulation in cancer, (2) which molecular players are involved in regulating SOX2 in cancer cells, and (3) what is the regulatory role of this transcription factor in a cancer context. To investigate these questions, I have generated CRISPR-mediated enhancer deletions in human cancer cell lines, which have shown significant loss of SOX2 expression. Through next generation sequencing, I identified SOX2 downstream targets that rely on this transcription factor to sustain transcription in cancer cells.

Embryonic development relies on stem cells and their differentiation into varying cell types, this process works by turning genes on or off in a specific time and space. Since all the cells in the body have an identical genome, there are regulatory elements within the DNA controlling gene expression and therefor cell identity. These elements are termed enhancers, and my project works to further understand these regions by assessing and modifying their sequences, epigenetic landscape, and surrounding chromatin in mouse embryonic stem cells. I have been able to create synthetic regulatory sequences that were confirmed in vitro, and I am now working towards testing these within a genomic context to uncover the regulatory code that enhancers follow. Common experiments I execute in the lab include CRISPR, ChIP-qPCR, cloning, and reporter assays.

Gene transcription is controlled in a precise spatial and temporal manner during development and this is known to be controlled by non-coding regulatory elements that can be located at kilobase to megabase distances from the genes they regulate. To properly regulate their cognate genes, enhancers need to be brought into close spatial proximity to them, however, the precise signals directing these long-range chromatin interactions are currently unknown. The goal of my project is to understand at the sequence level, what regulatory code is needed to direct these long-range interactions. To do this I will be using species sequence conservation data to direct CRISPR based chromatin modifications to alter chromatin topography.

The myometrium, a thick muscular layer of the uterine tissue, plays an important role in various reproductive functions along with a key role in labour. There has been remarkable progress towards understanding the physiology and clinical pathophysiology of the myometrium, however, the molecular mechanisms and genetic basis underlying its activity are very poorly understood. Gene regulation is a result of the complex interplay between transcriptional factors and regulatory regions within our DNA which allow the myometrium to transition into various phenotypes. My research project focuses on the role of these myometrium transcriptional factors and their regulation processes during the various stages of pregnancy and labour. For this, I aim to carry out experiments involving next generation sequencing techniques on myometrium tissue and conduct downstream genetic analysis.

MSc Candidates

Research Associate, Research Communications Officer

Past Lab Members

Lida Langroudi

PhD

Gurdeep Singh

PhD

Sakthi Moorthy

Postdoc

Gregor McEdwards

Harry Zhou

Master's

Anandi Bhattacharya

Master's

Mike Schwartz

Master's

Echo Jing

Virlana Shchuka

PhD

Fei Li

Navroop Dhaliwal

PhD

Nakisa Malek-Gilani

Master's

Julie Chih-yu Chen

Master's

Kevin Wang

Master's