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.

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.

Transcriptional enhancers, eRNAs, and epigenetic control of blood pressure. Many polygenic traits have been examined by genome wide association studies (GWAS) to identify different single nucleotide polymorphisms (SNPs) which contribute. Importantly, the majority of these SNPs lie within non-coding regions of the genome, making it a challenge to understand how they influence their trait. Our lab hypothesizes that noncoding SNPs operate through epigenetic mechanisms to regulate effector gene expression. We use blood pressure as a model since it is one of the most widely studied polygenic traits but also is a critical risk factor for cardiovascular disease, a leading killer in the developing world. In particular, our lab is focused on how different enhancers work to regulate gene expression through epigenetic mechanisms including chromatin looping, noncoding RNAs termed eRNAs, and histone epigenetics.

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.