The KRAB Zinc Finger Protein ZKSCAN3 binds to a SINE-embedded regulatory sequence to repress enhancer activity

KRAB Zinc Finger Proteins (KZFPs) are the largest family of transcription factors in mammals and are generally associated with the binding and repression of transposable elements. KZFPs use their KRAB domain to recruit the cofactor KAP1, which acts as a scaffold for the induction of heterochromatin, including SETDB1- mediated H3K9Me3. However, KZFPs are increasingly recognised as being integrated into gene regulatory networks through ‘domesticating’ transposable elements to act as cis-regulatory sequences. Zinc Finger with KRAB and SCAN domains 3 (ZKSCAN3) is a member of the KZFP family with poorly understood function. Here, I present data demonstrating that ZKSCAN3 binds to a SINE-embedded sequence localised at euchromatic enhancer sites. ZKSCAN3 is not associated with the induction of heterochromatin, but does act as a rheostat to negatively regulate the activity of enhancers. For the first time for a KZFP, I show that ZKSCAN3-mediated repression is independent of the KAP1 co-factor and of the KRAB domain. I go on to show that ZKSCAN3 is active during differentiation to the neural lineage and that it is necessary to control the proper expression level of dose-sensitive genes including those relating to axon guidance. This work contributes to the emerging understanding of how KZFPs partner up with TEs to regulate gene expression networks, and identifies ZKSCAN3 as a novel enhancer-binding factor functioning in development.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Moore, Daniel

Advisor dc:contributor.advisor

• Christophorou, Maria

• Transcription Factor
• KRAB Zinc Finger Proteins
• ZKSCAN3
• Enhancers
• Transposable elements

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f2273864-8d22-481c-8f5e-e6c643fda075/download
• http://purl.org/NET/rdflicense/allrightsreserved

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.119461

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/386092