June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
BAP1-mediated transcriptional influence on normal eye development
Author Affiliations & Notes
  • Christopher J Kaler
    University of Miami School of Medicine, Miami, Florida, United States
  • Daniel Rodriguez
    University of Miami School of Medicine, Miami, Florida, United States
  • Stefan Kurtenbach
    Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center, and Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, Miami, Florida, United States
  • J. William Harbour
    UT Southwestern Medical Center, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern, Dallas, Texas, United States
  • Footnotes
    Commercial Relationships   Christopher Kaler None; Daniel Rodriguez None; Stefan Kurtenbach None; J. William Harbour Castle Biosciences, Code C (Consultant/Contractor)
  • Footnotes
    Support  Research to Prevent Blindness Medical Student Eye Research Fellowship
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1891 – A0020. doi:
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    • Get Citation

      Christopher J Kaler, Daniel Rodriguez, Stefan Kurtenbach, J. William Harbour; BAP1-mediated transcriptional influence on normal eye development. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1891 – A0020.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Uveal Melanoma (UM) is an aggressive ocular cancer that leads to metastatic death in ≈50% of patients. UM can be divided into two prognostic groups based on molecular landscape: class 1 UM, associated with EIF1AX or SF3B1 variants and low metastatic risk, and class 2 UM with loss-of-function mutations in BAP1 [breast cancer type 1 (BRCA1)–associated protein 1]. BAP1 is known primarily as a tumor suppressor gene implicated in renal cell carcinoma as well as class 2 UM, and recently has been associated with the process of normal eye development. Related to this latter role, BAP1 normally interacts with HDAC1 (histone deacetylase subunit 1), a critical component of the NuRD (nucleosome remodeling and deacetylase) complex, which normally mediates embryonic lineage commitment and cell differentiation through DNA histone deacetylation and chromatin remodeling. Preliminary data from our laboratory strongly suggests that absence of BAP1 disrupts the normal association between HDAC1 and two NuRD complex proteins, CHD3 and CHD4 (Chromodomain Helicase DNA binding protein 3 and 4), DNA-binding proteins with helicase and nucleosome remodeling activities. Here, we further explore the impact of the BAP1-NuRD complex interaction by directly abrogating CHD3 and 4 and comparing downstream expression of biomarkers associated with BAP1 loss.

Methods : We remodeled HEK293 cells and normal melanocytes by siRNA knockdown of CHD3 and CHD4. We used Western blotting and densitometry to quantitate expression of HDAC4 (histone deacetylase subunit 4), a molecular signature of BAP1 loss, in these CHD3/CHD4 knockdown cells.

Results : Western blotting confirmed selective, efficient knockdown of CHD3 and CHD4. Western blots of HEK293 cells with CHD3 or CHD4 knockdown documented increased HDAC4 expression in both conditions compared to cells treated with an siRNA scramble as control. Experiments in progress include assessment of other molecular signatures of BAP1 loss, including the pluripotency marker NANOG, after siRNA knockdown of CHD3 and CHD4 in melanocytes.

Conclusions : These data support the potential involvement of BAP1 in recruitment of NuRD complex components and imply that differences in BAP1 expression may mediate transcriptional events involved in normal and abnormal eye development, via NuRD (Figure). Insights from this research may also be relevant to HDAC inhibitor therapy, previously suggested as promising treatment options for class 2 UM.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

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