Auxin-inducible degron 2 system deciphers functions of CTCF domains in transcriptional regulation

Hyle, Judith; Djekidel, Mohamed Nadhir; Williams, Justin; Wright, Shaela; Shao, Ying; Xu, Beisi; Li, Chunliang

doi:10.1186/s13059-022-02843-3

Cited by 7 publications

(5 citation statements)

References 91 publications

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“…In HSPC populations, ZNF143, SMC3, CTCF cistromes, and those of their known partners SMC1A, RAD21 and CHD8 62,65,66 , enrich over LTR41B elements (q≤3.22e-34, OR≤9.36) (Extended Data Fig. 5D, Extended Data Table 10), in line with the role in 3D chromatin organization of LTR41B elements 67 . The accessibility of TE subfamilies serving as docking sites for known HSC factors and/or chromatin interaction factors parallels the enrichment of the GATA1 and CTCF DNA recognition sequences at some of these TEs (Extended Data Fig.…”

Section: Accessible Te Subfamilies That Serve As Docking Sites For St...supporting

confidence: 57%

Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

Nadorp

Grillo

Qamra

et al. 2021

Preprint

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Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two thirds of patients will relapse with fatal disease within 5 years. AML is organized as a cellular hierarchy sustained by leukemia stem cells (LSC) at the apex, with LSC properties directly linked to tumor progression, therapy failure and disease relapse 1-5. Despite the central role of LSC in poor patient outcomes, little is known of the genetic determinants of their stemness properties 6-8. Although much AML research focuses on mutational processes and their impact on gene expression programs, the genetic determinants of cell state properties including stemness expand beyond mutations, relying on the genetic architecture captured in the chromatin of each cell 9-11. As LSCs share many functional and molecular properties with normal hematopoietic stem cells (HSC), we identified genetic determinants of primitive populations enriched for LSCs and HSCs in comparison with their downstream mature progeny by investigating their chromatin accessibility. Our work reveals how distinct transposable element (TE) subfamilies are used in primitive versus mature populations, functioning as docking sites for stem cell-associated regulators of genome topology, including CTCF, or lineage-specific transcription regulators in primitive and mature populations, respectively. We further show how TE subfamilies accessible in LSCs define docking sites for several oncogenic drivers in AML, namely FLI1, LYL1 and MEIS1. Using chromatin accessibility profiles from a cohort of AML patients, we further show the clinical utility of our TE accessibility-based LSCTE121 scoring scheme to identify patients with high rates of relapse. Collectively, our work reveals how different accessible TE subfamilies serve as genetic determinants of stemness properties in normal and leukemic hematopoietic stem cells.

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Section: Accessible Te Subfamilies That Serve As Docking Sites For St...supporting

confidence: 57%

Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

Nadorp

Grillo

Qamra

et al. 2021

Preprint

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“…The effect of dysfunctional chromatin looping and gene expression during development is a growing area of research however the exact mechanisms of pathogenicity in CRD remain to be uncovered (Lupiáñez et al, 2015 ; Hanssen et al, 2017 ; Chakraborty et al, 2023 ). One puzzle that remains is that fast depletion of CTCF , using auxin-inducible degron systems in cell-based models, have not resulted in dramatic changes to enhancer-promoter interactions or transcription, highlighting a tolerance within cell assays to CTCF loss (Alharbi et al, 2021 ; Hsieh et al, 2022 ; Hyle et al, 2023 ). However, when CTCF is depleted in vivo , it does produce severe developmental phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Hemizygous CTCF mice however, are viable and fertile, yet are predisposed to both spontaneous and induced tumor incidence, with global DNA methylation changes and deregulated gene expression patterns across tissues (Kemp et al, 2014 ; Alharbi et al, 2021 ). Depletion of CTCF in mammalian cell lines using the auxin-inducible degron system results in loss of chromatin looping and limited effects on gene transcription (Nora et al, 2017 ; Hyle et al, 2023 ). These studies highlight the necessity of correct CTCF gene dosage during development and throughout lifespan.…”

Section: Introductionmentioning

confidence: 99%

An updated catalog of CTCF variants associated with neurodevelopmental disorder phenotypes

Price,

Fedida,

Pugacheva

et al. 2023

Front. Mol. Neurosci.

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IntroductionCTCF-related disorder (CRD) is a neurodevelopmental disorder (NDD) caused by monoallelic pathogenic variants in CTCF. The first CTCF variants in CRD cases were documented in 2013. To date, 76 CTCF variants have been further described in the literature. In recent years, due to the increased application of next-generation sequencing (NGS), growing numbers of CTCF variants are being identified, and multiple genotype-phenotype databases cataloging such variants are emerging.MethodsIn this study, we aimed to expand the genotypic spectrum of CRD, by cataloging NDD phenotypes associated with reported CTCF variants. Here, we systematically reviewed all known CTCF variants reported in case studies and large-scale exome sequencing cohorts. We also conducted a meta-analysis using public variant data from genotype-phenotype databases to identify additional CTCF variants, which we then curated and annotated.ResultsFrom this combined approach, we report an additional 86 CTCF variants associated with NDD phenotypes that have not yet been described in the literature. Furthermore, we describe and explain inconsistencies in the quality of reported variants, which impairs the reuse of data for research of NDDs and other pathologies.DiscussionFrom this integrated analysis, we provide a comprehensive and annotated catalog of all currently known CTCF mutations associated with NDD phenotypes, to aid diagnostic applications, as well as translational and basic research.

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“…To scrutinize the detailed binding properties affected by CTCF R567W , we performed motif enrichment analysis on our ChIP-seq data using a previously described method 41 . Using brain tissues as an example, we categorized CTCF sites into four groups based on alterations in CTCF binding strength following the CTCF R567W mutation.…”

Section: Ctcf R567w Weakens Ctcf Binding To Sites With Upstream Motifsmentioning

confidence: 99%

CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment

Zhang,

Hu,

et al. 2024

Preprint

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The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations inCTCFhave been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explored the regulatory roles of a clinically relevant R567W point mutation, located within the 11thzinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567Wmutation exhibited growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single- cell transcriptome levels. This mutation induced premature stem-like cell exhaustion, accelerated the maturation of GABAergic neurons, and disrupted neurodevelopmental and synaptic pathways. Additionally, it specifically hindered CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrored the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567Wmutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.

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Auxin-inducible degron 2 system deciphers functions of CTCF domains in transcriptional regulation

Cited by 7 publications

References 91 publications

Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

An updated catalog of CTCF variants associated with neurodevelopmental disorder phenotypes

CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment

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