ABSTRACT
Paralog switching in chromatin remodeling complexes plays a key role in development and loss of regulatory
control over chromatin paralog functions is closely linked to many types of cancer. Human SIN3A and SIN3B
are amongst this class of important chromatin remodeling paralogs. SIN3A mutations are considered driver
mutations in uterine corpus endometrial carcinoma, and both SIN3A and SIN3B haploinsufficiency linked to
human neurodevelopmental disorders. Human SIN3A and SIN3B are members of several large multiprotein
complexes involved in chromatin remodeling containing the histone deacetylase enzymes HDAC1 and HDAC2.
While the overall members of the SIN3A and SIN3B complexes is largely known, the structure and function of
specific complexes in these networks remain poorly understood. Furthermore, the precise targeting of gene
repression by SIN3/HDAC-mediated histone deacetylation is likely controlled by the non-catalytic SIN3 subunits
but also remains enigmatic. These fundamental gaps in knowledge regarding the structure and function of SIN3A
and SIN3B containing complexes limit our ability to devise specific therapeutic interventions in cancer, for
example. The overarching goal of the research in the laboratory is to understand the molecular mechanisms of
how specific SIN3A and SIN3B complexes regulate gene expression and chromatin remodeling in normal and
diseased human conditions. We are in a unique position to advance the understanding of these area of research
based on my strong track record and long-standing expertise in chromatin remodeling and proteomics,
assembled team of collaborators, and multidisciplinary approach. In our lab, we continually develop new
proteomic technologies and apply them to chromatin remodeling complexes and networks. Here, we will use a
comprehensive approach of affinity purification, enzyme kinetics, peptide synthesis, fluorescence microscopy,
genomics, quantitative proteomics, cross linking mass spectrometry, and integrative structural modeling. Using
these methodologies over the next five years, we will investigate 1) How are SIN3A and SIN3B complexes
assembled, 2) What are the regulatory functions of specific subunits, 3) How do SIN3A complexes regulate
specific transcription factor function, 4) What are the SIN3A and SIN3B networks in endometrial cells, and 5)
How can we disrupt protein protein interactions in these complexes? This set of questions will go from a
fundamental structure and function of these complexes to determining the role of specific complexes in important
human cellular models. We will lay the foundation to address the gap in knowledge in the diversity and function
of specific chromatin remodeling complexes. In addition, we will begin to develop new therapeutic strategies to
target specific chromatin remodeling complexes. With this information in hand, we will be closer to our long-term
goal and vision of designing peptide-based approaches to disrupt specific protein complexes as novel and
specific cancer therapeutic agents.
