# Transcriptional Control of the Mouse aA-crystallin locus

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $417,500

## Abstract

ABSTRACT
The long-term goal of this research program is to elucidate the global mechanisms that coordinately
regulate the expression of genes required for the development and differentiation of the ocular lens. Since
the lens is a simple tissue composed of only two mature cell types, elucidation of these mechanisms
provides insight into those processes required for the differentiation of far more complex tissues and
provides the groundwork for the development and design of cutting-edge new avenues of biological
research ranging from stem-cell replacement therapies to targeted cancer treatments. The central premise
of this proposal is that differentiation of lens cells is dependent on the coordinated interactions of DNA-
binding transcription factors with FGF and BMP signal transduction pathways to orchestrate lens-specific
expression of hundreds of genes required to form the mature eye lens. The hallmark of mammalian lens
fiber cell differentiation is accumulation of a- and b-/g-crystallins as key lens structural and protective
proteins, cellular elongation, and degradation of nuclei and other organelles. In differentiating lens, specific
groups of genes are transcriptionally turned on and off, and the central part of this process is controlled
through the accessibility of chromatin DNA to associate with transcription factors and chromatin
remodeling enzymes. Among these factors, c-Maf, Pax6, Prox1, c-Jun, Etv5, and Smads, act together as
a unit to systematically regulate the spatial and temporal expression of individual crystallins and other
genes essential for the differentiation and function of the eye lens. Specifically, this proposal will: 1)
elucidate the functional role that chromatin plays in regulating lens differentiation-specific gene expression
at the genome-wide level, (2) define the specific roles of DNA-binding transcription factors and their roles
in formation of “open” chromatin regions during lens differentiation, and (3) identify and characterize the
role and function of distinct topologically associating domains (TADs) in lens cell nuclei, including
transcriptional factories, nucleoli and splicing speckles, as critical components of the lens differentiation.
The proposed studies are supported by strong preliminary data demonstrating the formation of “open”
regions of chromatin in the promoters and enhancers of key lens differentiation genes allowing
accessibility and function of essential transcription factors and the identification of discrete TADs
comprised of crystallin loci from different chromosomes to coordinate their expression in lens fiber cells.
The results will define for the first time those sequential events required for lens-specific gene expression
through the interplay between transcription factors and altered chromatin conformation, will provide novel
insights into the 3D-organization of lens fiber cell nuclei that are required for lens differentiation, and
uncover novel regulatory mechanisms that drive lens f...

## Key facts

- **NIH application ID:** 9918892
- **Project number:** 5R01EY014237-20
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Ales Cvekl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,500
- **Award type:** 5
- **Project period:** 2003-04-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918892

## Citation

> US National Institutes of Health, RePORTER application 9918892, Transcriptional Control of the Mouse aA-crystallin locus (5R01EY014237-20). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9918892. Licensed CC0.

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