The Transition from Quiescent to Activated States in Human Hematopoietic Stem Cells is Governed by Dynamic 3D Genome Reorganization

Takayama, Nobuki; Murison, Alex; Takayanagi, Shin‐ichiro; Arlidge, Christopher; Zhou, Stanley; Prat, Laura Garcia; Chan-Seng-Yue, Michelle; Zandi, Sasan; Gan, Olga I.; Boutzen, Héléna; Kaufmann, Kerstin B.; Trotman-Grant, Aaron C.; Schoof, Erwin M.; Kron, Ken J.; Díaz, Noèlia; Lee, John J.Y.; Medina, Tiago da Silva; Carvalho, Daniel D. De; Taylor, Michael D.; Vaquerizas, Juan M.; Xie, Stephanie Z.; Dick, John E.; Lupien, Mathieu

doi:10.2139/ssrn.3611286

Cited by 12 publications

(31 citation statements)

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“…shRNA-mediated knockdown of CTCF in LT-HSCs prevents their exit from quiescence and induces transcriptional changes consistent with the maintenance of stemness 51 . Because of the correlation of the repression of MECOM down genes upon HSC activation by chromatin looping mediated by CTCF, we hypothesized that CTCF perturbation would lead to increased expression of MECOM down genes.…”

Section: Resultsmentioning

confidence: 95%

“…Next, we performed aggregate peak analysis (APA) to compare the genomic organization of the MECOM down genes upon early exit from quiescence by integrating Low-C chromatin interaction data from phenotypic LT-HSCs and ST-HSCs 51 . Using all 7,358 common chromatin loops, there was significant enrichment of chromatin interaction apices in both LT-HSCs and ST-HSCs, as previously observed 51 , but there was no significant difference between LT-HSCs and ST-HSCs. Notably, analysis of the chromatin loops of CTCF footprint-containing cis REs associated with MECOM down genes revealed significantly stronger chromatin interactions in ST-HSCs compared to LT-HSCs.…”

Section: Resultsmentioning

confidence: 99%

“…Spatial orientation of neighboring motifs is crucial to the function of CTCF, and TAD boundaries are marked by divergent CTCF motifs. Within TADs, convergent CTCF sites co-occur with motifs of lineagedefining TFs and mediate cisRE-promoter interactions 69 . Recently, CTCF has been implicated in regulating the exit of HSCs from quiescence by altering looping and helping to silence key stemness genes 70 and dynamic CTCF binding cooperates with lineage-defining TFs during hematopoietic differentiation 69 .…”

Section: Dynamic Ctcf Binding During Hsc Activation Represses Mecom Down Genesmentioning

confidence: 99%

“…Within TADs, convergent CTCF sites co-occur with motifs of lineagedefining TFs and mediate cisRE-promoter interactions 69 . Recently, CTCF has been implicated in regulating the exit of HSCs from quiescence by altering looping and helping to silence key stemness genes 70 and dynamic CTCF binding cooperates with lineage-defining TFs during hematopoietic differentiation 69 . Therefore, we hypothesized that CTCF plays a role in mediating the differential expression of MECOM down genes following loss of MECOM.…”

Section: Dynamic Ctcf Binding During Hsc Activation Represses Mecom Down Genesmentioning

confidence: 99%

“…As representative examples, we visualized chromatin looping at the genomic loci of two MECOM down genes, MLLT3 and MEF2C. MLLT3 is a crucial regulator of HSC self-renewal 42 and MEF2C is highly expressed in HSCs and is an important factor involved in cell fate decisions 69 . Both gene loci show increased chromatin looping upon the transition from LT-HSCs to ST-HSCs (Fig.…”

Section: Dynamic Ctcf Binding During Hsc Activation Represses Mecom Down Genesmentioning

confidence: 99%

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A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

Voit

Tao

et al. 2021

Preprint

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The molecular regulation of human hematopoietic stem cell (HSC) self-renewal is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC self-renewal. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs exit quiescence. Strikingly, we show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Dynamic Ctcf Binding During Hsc Activation Represses Mecom Down Genesmentioning

confidence: 99%

Section: Dynamic Ctcf Binding During Hsc Activation Represses Mecom Down Genesmentioning

confidence: 99%

Section: Dynamic Ctcf Binding During Hsc Activation Represses Mecom Down Genesmentioning

confidence: 99%

See 3 more Smart Citations

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

Voit

Tao

et al. 2021

Preprint

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A primary hierarchically organized patient-derived model enables in depth interrogation of stemness driven by the coding and non-coding genome

et al. 2022

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Many cancers are organized as cellular hierarchies sustained by cancer stem cells (CSC), whose eradication is crucial for achieving long-term remission. Difficulties to isolate and undertake in vitro and in vivo experimental studies of rare CSC under conditions that preserve their original properties currently constitute a bottleneck for identifying molecular mechanisms involving coding and non-coding genomic regions that govern stemness. We focussed on acute myeloid leukemia (AML) as a paradigm of the CSC model and developed a patient-derived system termed OCI-AML22 that recapitulates the cellular hierarchy driven by leukemia stem cells (LSC). Through classical flow sorting and functional analyses, we established that a single phenotypic population is highly enriched for LSC. The LSC fraction can be easily isolated and serially expanded in culture or in xenografts while faithfully recapitulating functional, transcriptional and epigenetic features of primary LSCs. A novel non-coding regulatory element was identified with a new computational approach using functionally validated primary AML LSC fractions and its role in LSC stemness validated through efficient CRISPR editing using methods optimized for OCI-AML22 LSC. Collectively, OCI-AML22 constitutes a valuable resource to uncover mechanisms governing CSC driven malignancies.

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A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia

Zeng

Bansal

Jin

et al. 2022

Nat Med

153

119

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The treatment landscape of AML is evolving with promising therapies entering clinical translation, yet patient responses remain heterogeneous and biomarkers for tailoring treatment are lacking. To understand how disease heterogeneity links with therapy response, we determined the leukemia cell hierarchy make-up from bulk transcriptomes of over 1000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor, and mature cell types. Leukemia hierarchy composition was associated with functional, genomic, and clinical properties and converged into four overall classes, spanning Primitive, Mature, GMP, and Intermediate. Critically, variation in hierarchy composition along the Primitive vs GMP or Primitive vs Mature axes were associated with response to chemotherapy or drug sensitivity profiles of targeted therapies, respectively. A 7-gene biomarker derived from the Primitive vs Mature axis was predictive of patient response to 105 investigational drugs. Thus, hierarchy composition constitutes a novel framework for understanding disease biology and advancing precision medicine in AML.

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The Transition from Quiescent to Activated States in Human Hematopoietic Stem Cells is Governed by Dynamic 3D Genome Reorganization

Cited by 12 publications

References 0 publications

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

A primary hierarchically organized patient-derived model enables in depth interrogation of stemness driven by the coding and non-coding genome

A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia

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