# FUNCTIONAL GENOMICS AND MECHANISM OF BCL11B ACTION IN LYMPHOCYTE COMMITMENT

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2022 · $632,343

## Abstract

ABSTRACT/PROJECT SUMMARY
 Bcl11b is a bifunctional zinc finger transcription factor that is crucial for the lineage commitment of TCRαβ T
cells. The Bcl11b gene is activated precisely at the developmental transition when the cells undergo
commitment, and it sustains αβ T-cell identity and functions of multiple T-cell subsets thereafter. Genes that it
keeps silent during initial T-cell commitment include key regulators of all innate lymphoid cells (ILCs) and natural
killer cells (NK). Some of these genes are also continuously repressed by Bcl11b in mature T cells. However,
surprisingly, Bcl11b is also expressed in one particular class of innate lymphoid cells, ILC2 cells. ILC2 cells also
require Bcl11b for their identity, yet at the same time, they express Bcl11b along with Id2 and other genes that
Bcl11b normally silences in T cells. A major question is how Bcl11b works so differently in ILC2 and early
developing T cells (pro-T cells). We propose to determine how this works using functional genomics and gene
network dissection to shed light on the mechanisms that make the difference.
 Our preliminary evidence from ChIP-seq and proteomic analyses shows that Bcl11b binds to distinct, only
partially overlapping sets of sites in the two cellular contexts, and interacts with different transcriptional partners;
and this is correlated with regulation of almost completely nonoverlapping sets of Bcl11b-sensitive genes in the
two contexts. To interpret these differences, we first distinguish functional from probably-nonfunctional sites
where Bcl11b binds DNA, by identifying its impact on complexes of co-regulators that assemble with it. Thus,
the subset of sites is mapped where Bcl11b has a locally indispensable nucleation role for chromatin-modulating
cofactors and/or other specific interaction partners. Second, we plan to map genomic regions where higher-order
chromatin looping interactions and compartment boundaries can also be shown to depend on Bcl11b expression.
These results will identify the Bcl11b binding sites in each cell context where that binding is molecularly
functional. To determine the underlying causes of these differences, we will test how Bcl11b's own site binding
preferences may be established through the presence of other transcription factors. We have identified at least
two other important sequence-specific transcription factors, e.g., that (1) interact extensively with Bcl11b at many
of its binding sites in the T-cell context, yet (2) are under-represented in ILC2 cells. Using retroviral transduction
and CRISPR technology adapted to pro-T cells, we will introduce or delete putative interaction partners
reciprocally in ILC2 and pro-T cells, to evaluate critically what roles they may have in guiding the binding and
function of Bcl11b. We will apply this approach to explain how Bcl11b nucleates functionally different sites in
pro-T cells and ILC2s. Finally, an interaction of particular importance is the gene network circuit through wh...

## Key facts

- **NIH application ID:** 10393519
- **Project number:** 5R01AI135200-05
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** ELLEN V. ROTHENBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $632,343
- **Award type:** 5
- **Project period:** 2018-05-04 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393519

## Citation

> US National Institutes of Health, RePORTER application 10393519, FUNCTIONAL GENOMICS AND MECHANISM OF BCL11B ACTION IN LYMPHOCYTE COMMITMENT (5R01AI135200-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10393519. Licensed CC0.

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