Integrator functions in development and disease
Integrator is a multi-subunit complex stably associated with the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII). It was discovered in 2005 in our lab. We have uncovered multifaceted functions of Integrator in the regulation of essential biological activities:
- Processes of non-coding RNAs, including small nuclear RNAs (snRNAs) and enhancer RNAs (eRNAs).
- Coordinates transcriptional initiation and pause release during epidermal growth factor (EGF) stimulation at enhancers and immediate early gene promoters.
- Acts as a crucial transcriptional coactivator in MAPK signaling pathway.
We keep advancing our knowledge of Integrator complex on these fundamental questions:
- Dissect the structure of Integrator complex, and understand unique functions of individual Integrator subunit.
- Identify novel interacting partners of Integrator in response to different cell stimulus and in different subcellular compartments.
- Elucidate common mechanisms of Integrator in relaying activation signals from signaling pathways to target gene promoters.
- Investigate Integrator’s role in 3′ end processing of mRNAs.
- Understand Integrator’s functions in regulating global chromatin dynamics.
Our ultimate goal is to understand the biological consequences of Integrator mutation or perturbation in normal cell and development, and how to manipulate Integrator functions to treat diseases. We will use animal models and patient samples to understand Integrator’s roles in:
- Neural system development and brain functions.
- Hematopoietic development and leukemogenesis.
- Embryonic stem cell differentiation.
- Pancreatic cancer progression.
- Melanoma drug resistance.