Versiti - Sridhar Rao Laboratory | Versiti Blood Research Institute

Sridhar Rao Laboratory

The central focus of my laboratory is to understand how changes in gene expression ultimately lead to cell-fate decisions.

Sridhar Rao Laboratory at Versiti Blood Research Institute


Stem Cell Biology and Leukemia Research at Versiti Blood Research Institute

The ability of a single blood stem cell (called hematopoiesis) allows all of us to have all the blood cells we need for our lifetime. Problems with this process can result in a range of blood diseases but also the development of blood cancer(s) or leukemia. A large number of investigators at the BRI focus on these types of questions, allowing us to synergize. In particular, interactions between our Lab, John Pullikkan’s, Nan Zhu’s, and Karen Carlson's have allowed us to work together on a range of projects focused on Acute Myeloid Leukemia (AML).

The central focus of my laboratory is to understand how changes in gene expression ultimately lead to cell-fate decisions (Figure 1).

The precise control of cell-fate changes are required for normal development and aberrations in the process can lead to diseases including cancer.

Stem Cell Differentiation

Stem cells are capable of differentiating into other types of stem cells. For example, hematopoietic stem cells (HSCs) can divide and differentiate into all the different blood cell lineages such as red cells, white cells, and platelets. This process is coordinated by changes in gene expression, in which a subset of genes need to go UP in their expression, and a different subset need to go DOWN. Aberrations in this process can cause not enough differentiated cells to be made, but also ultimately lead to cancers such as leukemia. All aspects of gene expression are controlled by two types of factors. Trans-acting factors, suc as DNA-binding proteins like transcription factors which then bind DNA segments called cis-regulatory elements.

Stem Cell DifferentiationFigure 1: Stem Cell Differentiation Illustration

Enhancer Function

Specifically, our lab is focused how cis-regulatory elements (CREs) which are located far away from the genes they regulate operate (Figure 2). These distal CREs, globally referred to as enhancers, play a central role in regulating gene expression in a temporal and cell-type specific manner. The long-term goal of our lab is to understand how these CREs regulate both normal mammalian development, but also how mutations which prevent proper enhancer function cause diseases including leukemia.

distal CREs (enhancers)Figure 2: distal CREs (enhancers) illustration

A schematic illustrating how distal CREs (enhancers) are brought into close physical contact within the nucleus with the genes they regulate through a process termed chromatin looping. The looping is mediated by both CTCF and the cohesin complex.

Enhancers themselves are bound by the transcription factors (TFs) and the histone acetyltransferase CBP. In addition, highly active enhancers are transcribed by RNA Pol II to produce long non-coding RNAs called eRNAs.

Project 1

Transcriptional enhancers, eRNAs, and molecular control of early mammalian development. During the development of mammals from a single fertilized egg, there are rapid changes in both the number and types of cells present.  The earliest types of cells which give rise to the embryo proper are termed pluripotent, because of their ability to differentiate into all three primitive germ layers.  Using these pluripotent cells from mice, we can investigate how these cells differentiate into all the different cell types.  In particular, our lab is focused on how different enhancers work collaboratively to regulate gene expression in normal pluripotent cells but also as they differentiate.  Second, we focus on how the eRNAs which arise from highly active enhancers may regulate gene expression.

Project 2

The molecular mechanism of cohesin complex mutations in cancer. The cohesin complex plays a central role in gene expression by facilitating and stabilizing chromatin loops which permits enhancers to be brought into close physical proximity of the genes they regulate within the nucleus. Importantly, mutations within core cohesin complex subunits (STAG2, SMC3, SMC1A, RAD21) are found in 10-20% of patients with Acute Myeloid Leukemia (AML).  Our lab is focused on understanding how these mutations promote leukemia development, but also how they interact with own known leukemic drivers.

  1. Genomic Editing with CRISPR/Cas9: Dr. Rao is the scientific director of the BRI’s Genomic Editing core, and has a wealth of experience with this powerful emerging technology.
  2. Transcriptomics: Dr. Rao’s lab uses both bulk and single cell RNA-seq to explore genome-wide changes in expression. In particular, his lab has a dedicated bioinformatics analyst, but trainees are expected to learn how to analyze these types of datasets independently.
  3. Epigenomics: Our lab has used various forms of chromatin immune oprecipitations could with sequencing (ChIP-seq) to interrogate changes in chromatin marks known to be critical to gene expression. More recently, our lab has adopted CUT&Tag (Hatice et al, Nat Communication, 2019; PMC6488672).
  4. Animal models: We use a large number of genetically-modified mice to understand how leukemia develops in vivo.

View selected publications and datasets in the resources section.

Full Publication List

Complete List of Published Work in NCBI My Bibliography.

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