Dr. Malik studies regulation of gene expression in eukaryotic cells. Building on the work of Rockefeller’s Robert G. Roeder, his research has contributed to the concept that transcription of messenger RNA genes by RNA polymerase II is a multistep process controlled by the orchestrated action of numerous factors. These include general transcription factors as well as tissue- and gene-specific factors, which respond to various cellular signals and bind to specific DNA sequences to regulate RNA polymerase II activity. Efficient functional coupling of activators and the general machinery is now known to be largely achieved through the multisubunit Mediator coactivator complex. Working in Dr. Roeder’s group, Dr. Malik was among the first to isolate and structurally and functionally characterize the Mediator complex.
In recent work, Dr. Malik’s group has focused on Mediator-dependent transcriptional mechanisms at loci regulated by the nuclear receptor HNF4α, a critical regulator of liver organogenesis and physiology. Dr. Malik’s research emphasizes reconstitution of HNF4α– and Mediator-regulated transcription in vitro and biochemical dissection of the underlying mechanisms. Most recently, his group established a system reconstituted from homogeneously pure components in which transcription of a model liver gene occurs in the context of nucleosomes that package cellular DNA. This system revealed a cascade of novel Mediator-controlled steps in the transcription pathway. Overall, evidence from Dr. Malik’s group, as well as from other laboratories, has highlighted the central role of Mediator in controlling the expression programs of individual genes by acting as an “integrative hub” that both assimilates the multiple signals feeding into the gene and modulates the appropriate transcriptional response.