Co-occupancy Identifies Transcription Factor Co-operation for Axon Growth

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 6

PMID 33953205

Citations 8

Authors

Ishwariya Venkatesh

Vatsal Mehra

Zimei Wang

Matthew T Simpson

Erik Eastwood

Advaita Chakraborty

Zac Beine

Derek Gross

Michael Cabahug

Greta Olson

Murray G Blackmore

Affiliations

Soon will be listed here.

Abstract

Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease. Because TFs often depend on cooperative activity, a major challenge is to identify and deploy optimal sets. Here we developed a bioinformatics pipeline, centered on TF co-occupancy of regulatory DNA, and used it to predict factors that potentiate the effects of pro-regenerative Klf6 in vitro. High content screens of neurite outgrowth identified cooperative activity by 12 candidates, and systematic testing in a mouse model of corticospinal tract (CST) damage substantiated three novel instances of pairwise cooperation. Combined Klf6 and Nr5a2 drove the strongest growth, and transcriptional profiling of CST neurons identified Klf6/Nr5a2-responsive gene networks involved in macromolecule biosynthesis and DNA repair. These data identify TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics approach to detect TF cooperation.

Citing Articles

The transcription factor combination MEF2 and KLF7 promotes axonal sprouting in the injured spinal cord with functional improvement and regeneration-associated gene expression.

Attwell C, Maldonado-Lasuncion I, Eggers R, Bijleveld B, Ellenbroek W, Siersema N Mol Neurodegener. 2025; 20(1):18.

PMID: 39923113 PMC: 11807332. DOI: 10.1186/s13024-025-00805-4.

Single-Nuclei Sequencing Reveals a Robust Corticospinal Response to Nearby Axotomy But Overall Insensitivity to Spinal Injury.

Wang Z, Kumaran M, Batsel E, Testor-Cabrera S, Beine Z, Alvarez Ribelles A J Neurosci. 2025; 45(8).

PMID: 39746824 PMC: 11841758. DOI: 10.1523/JNEUROSCI.1508-24.2024.

Injury distance limits the transcriptional response to spinal injury.

Wang Z, Kumaran M, Batsel E, Testor-Cabrera S, Beine Z, Alvarez Ribelles A bioRxiv. 2024; .

PMID: 38854133 PMC: 11160615. DOI: 10.1101/2024.05.27.596075.

Patterns of transcription factor binding and epigenome at promoters allow interpretable predictability of multiple functions of non-coding and coding genes.

Chandra O, Sharma M, Pandey N, Jha I, Mishra S, Kong S Comput Struct Biotechnol J. 2023; 21:3590-3603.

PMID: 37520281 PMC: 10371796. DOI: 10.1016/j.csbj.2023.07.014.

SnRNA-seq reveals the heterogeneity of spinal ventral horn and mechanism of motor neuron axon regeneration.

Zhu Y, Luan C, Gong L, Gu Y, Wang X, Sun H iScience. 2023; 26(8):107264.

PMID: 37502257 PMC: 10368823. DOI: 10.1016/j.isci.2023.107264.

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