Research

Our lab seeks to understand the mechanisms of signal-responsive gene expression with a focus on the Notch signaling pathway.

Notch Signaling

The Notch signaling pathway is one of the major conserved signaling pathways in humans, allowing cells in direct contact with each other to communicate. Notch signaling is involved in the development and homeostasis of multiple organ systems in the human body, and dysregulation of this pathway is associated with multiple types of cancer.

Upon activation by ligand binding, the Notch receptor is cleaved at the membrane and the intracellular domains of Notch (ICN) are released and transit into the nucleus. ICN then forms the Notch transcriptional complex with the DNA binding protein RBPJ and a coactivator of the MAML family. This complex then promotes transcription of Notch target genes. Interestingly, Notch promotes expression of different target genes in different cellular contexts, allowing it to have a variety of outputs in cell types throughout the body.

Our goal is to better understand the mechanisms underlying cell-type specific Notch-dependent transcription. We combine a variety of approaches, including biochemistry, molecular biology, structural biology, and functional genomics to comprehensively address this question at the molecular level.

How does Notch activation promote transcription?

In Dr. Roger's postdoctoral work, she showed that Notch activation activates transcription primarily by promoting the relase of paused RNA Polymerase II at the promoters of Notch target genes. Currently, we are investigating if this mechanism is universal across different cellular contexts where Notch signaling is important, such as T-ALL cancer cell lines.

Additionally, we are investigating how Notch activation promotes pause release, and identifying which transcriptional cofactors are recruited to the Notch transcriptional complex in different cellular contexts.

AlphaFold predicted structure of MAML1

How do transcriptional activation domains interact with cofactors?

Coactivators of the MAML family are a required component of the Notch transcriptional complex, the most well-studied of which is MAML1. MAML proteins are thought to recruit transcriptional cofactors, such as p300, to the genome to promote transcription. As is true for many transcriptional effectors, MAML1 is largely predicted to be intrinsically disordered, and is not known to form stable globular domains. The Rogers labs aims to understand how the protein sequence of MAML1 contributes to its function as a coactivator, as a model system for understanding intrinsically disordered transcriptional effectors. Which portions of MAML1 are required for activation of Notch target genes? How do these segments specifically interact with recruited cofactors? What is the role of intrinsically disordered segments of MAML1 in gene activation? We will take an interdisciplinary approach to address these questions, combining functional genomics with biochemistry and structural biology.

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