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Updated: Oct 21, 2025

Mapping Mammalian 3D Genome Interactions with Micro-C-XL
Published on: November 3, 2023
A prelude to the proximity interaction mapping of CXXC5
Gamze Ayaz1,2, Gizem Turan3, Çağla Ece Olgun3
1Department of Biological Sciences, Middle East Technical University, 06800, Ankara, Turkey. gamze.ayazsen@nih.gov.
Abstract:
CXXC5 is a member of the zinc-finger CXXC family proteins that interact with unmodified CpG dinucleotides through a conserved ZF-CXXC domain. CXXC5 is involved in the modulation of gene expressions that lead to alterations in diverse cellular events. However, the underlying mechanism of CXXC5-modulated gene expressions remains unclear. Proteins perform their functions in a network of proteins whose identities and amounts change spatiotemporally in response to various stimuli in a lineage-specific manner. Since CXXC5 lacks an intrinsic transcription regulatory function or enzymatic activity but is a DNA binder, CXXC5 by interacting with proteins could act as a scaffold to establish a chromatin state restrictive or permissive for transcription. To initially address this, we utilized the proximity-dependent biotinylation approach. Proximity interaction partners of CXXC5 include DNA and chromatin modifiers, transcription factors/co-regulators, and RNA processors. Of these, CXXC5 through its CXXC domain interacted with EMD, MAZ, and MeCP2. Furthermore, an interplay between CXXC5 and MeCP2 was critical for a subset of CXXC5 target gene expressions. It appears that CXXC5 may act as a nucleation factor in modulating gene expressions. Providing a prelude for CXXC5 actions, our results could also contribute to a better understanding of CXXC5-mediated cellular processes in physiology and pathophysiology.
Insights
CXXC5 protein binds DNA and interacts with other proteins to regulate gene expression. This study identifies key interaction partners, like MeCP2, revealing CXXC5
Area of Science:
- Molecular Biology
- Epigenetics
- Gene Regulation
Background:
- CXXC5 is a DNA-binding protein in the zinc-finger CXXC family, implicated in gene expression modulation.
- The precise mechanisms by which CXXC5 influences gene expression remain largely unknown.
- Proteins function in dynamic networks, suggesting CXXC5 may act as a scaffold for regulatory complexes.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying CXXC5-mediated gene expression.
- To identify CXXC5 interaction partners involved in its regulatory functions.
- To understand CXXC5's role in establishing chromatin states for transcription.
Main Methods:
- Employed proximity-dependent biotinylation to identify CXXC5 interaction partners.
- Investigated interactions between CXXC5 and identified proteins using molecular assays.
- Assessed the functional significance of CXXC5-protein interplay on target gene expression.
Main Results:
- Identified DNA and chromatin modifiers, transcription factors, and RNA processors as CXXC5 proximity interactors.
- CXXC5 directly interacts with EMD, MAZ, and MeCP2 via its CXXC domain.
- The interaction between CXXC5 and MeCP2 is crucial for the expression of a subset of CXXC5 target genes.
Conclusions:
- CXXC5 functions as a scaffold protein, potentially acting as a nucleation factor in gene expression modulation.
- The interplay between CXXC5 and MeCP2 is a key mechanism in regulating specific gene expressions.
- Findings provide insights into CXXC5's role in cellular processes and disease pathophysiology.
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