# Characterization of the Integrator-Z3 module as a regulator of neuronal differentiation

> **NIH NIH F31** · UNIVERSITY OF ROCHESTER · 2024 · $48,974

## Abstract

Abstract
 Transcriptional regulation is an essential process for proper development that a host of cellular machinery
orchestrates. Among these cellular factors is the Integrator complex (INT), a 17-subunit complex that associates
with paused RNA polymerase II and is responsible for the 3'-end processing of non-coding RNAs and premature
termination of promoter-proximally paused RNAPII. Consistent with a fundamental role of Integrator function,
mutations within INT subunits cause neuronal dysfunction, including complex neurological syndromes marked
by cerebellar ataxia, intellectual defects, and seizures. Similarly, three zinc finger proteins comprising the ‘Z3
Complex’ (ZNF592, ZNF687, and ZMYND8) thought to be associated with INT also have diverse neurological
phenotypes when genetically perturbed. Despite a fundamental requirement of Integrator for gene expression
and apparent overlap of neurological symptoms in patients with mutations in INT and Z3 subunits, the molecular
basis of this profound connection between Z3-INT and brain disorders is unknown. My preliminary biochemical
purifications and proteomics described below indicate that the Z3 complex is strongly bound to INT. The formation
of a Z3-INT complex indicates that specific DNA binding proteins can potentially influence INT recruitment to
promoter-proximal regions in the genome. Consistently, my RNA-sequencing analyses from cells depleted of Z3
subunits reveal broad transcriptional changes that significantly overlap with changes observed upon depletion
of INT subunits. Nothing is known about Z3-INT subunit occupancy during neurogenesis nor how perturbation
of Z3-INT expression would affect neural development. This is despite the compelling human patient phenotypes
caused by their mutation revealing their importance to brain development. Based on these data, I hypothesize
that Z3 interacts with INT to modulate its recruitment and occupancy to promoters, and perturbation of this
process leads to disrupted neuronal differentiation. To address this, I will first determine expression and
occupancy of Z3-INT during neuronal differentiation. Second, I will elucidate the functional role of Z3-INT
neuronal fitness. Third, I will uncover biochemical interactions between Z3 and INT. Completion of these aims
will converge to uncover the link between INT and associated transcription factors, Z3.

## Key facts

- **NIH application ID:** 10995745
- **Project number:** 1F31NS139499-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** MaryClaire Haseley
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995745

## Citation

> US National Institutes of Health, RePORTER application 10995745, Characterization of the Integrator-Z3 module as a regulator of neuronal differentiation (1F31NS139499-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10995745. Licensed CC0.

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