Ali Shilatifard

Biosketch

In 1996, Shilatifard established the first link between transcriptional elongation control and cancer. He biochemically demonstrated that the ELL gene, a translocation partner of MLL gene found in leukemia, regulates transcription elongation. Based on this finding, he proposed that transcriptional elongation is a key regulatory step in gene expression and its misregulation can result in disease pathogenesis. His lab later proved this original model by identifying that many of the MLL fusion partners found in leukemia are components of the ELL-containing Super Elongation Complex (SEC), which promote transcriptional elongation through its kinase subunit CDK9. These findings confirmed that altered transcription elongation contributes to cancer, leading to proposed therapeutic approaches from Shilatifard laboratory.

In parallel, Shilatifard’s team identified SET1, the yeast homolog of trithorax and MLL, as the catalytic subunit of COMPASS (Complex Proteins Associated with SET1)—which his lab purified as the first histone H3K4 methyltransferase. His lab then purified COMPASS family members in Drosophila and mammals, revealing how this complex regulates transcription through H3K4 methylation and orchestrating developmental gene expression. Cancer genome sequencing since has uncovered frequent mutations in COMPASS subunits in cancer and other developmental disorders. Building on these discoveries, Shilatifard’s lab developed therapeutic strategies targeting COMPASS and its gene targets, with some advancing to FDA-approved clinical trials for cancer treatment.

Research Interests

Ongoing and future research in the Shilatifard lab is focused on elucidating the mechanisms of gene- and locus-specific transcriptional elongation control. These studies aim to define how cells and tissues interpret environmental cues and developmental signals to modulate gene expression in a locus- and gene-specific manner. Despite significant advances, it remains unclear how subsets of genes are selectively activated in response to stimuli via the kinase activity of CDK9, a core component of the Super Elongation Complex (SEC) and BRD4 complexes. Previous work from the Shilatifard lab demonstrated that the BRD4/CDK9 complex is dispensable for transcriptional induction during heat shock, where SEC is essential, while hypoxic responses depend on BRD4/CDK9 but are independent of SEC. Ongoing studies aim to further dissect these context-dependent mechanisms of transcriptional elongation control.

To this end, the lab has employed biochemical purification techniques and genetic strategies for acute protein depletion to investigate locus-specific transcriptional regulation. Recently, after over 14 years of development, the lab introduced TurboCas, a novel method enabling locus-specific labeling of genomic regions and isolation of their associated protein interactomes, allowing high-resolution analysis of mechanisms governing gene- and locus-specific transcriptional regulation. These investigations aim to define the precise roles of transcriptional elongation control and to understand how mutations or disruptions in transcriptional and epigenetic pathways contribute to disease.