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; García‐Prat, Laura; 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:10.1016/j.stem.2020.11.001

Cited by 62 publications

(79 citation statements)

References 53 publications

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“…Fig 2d). In agreement with these results, MER57B1, MER57B2 and LTR67B subfamilies showed the highest Z-scores in the LT/HSPC signature of chromatin accessibility previously reported to discriminate long-term from shortterm self-renewing and other progenitor populations 16 compared to all other hematopoietic chromatin accessibility signatures (Suppl. Table 6).…”

Section: Accessible Tes As Docking Sites For Stem Factorssupporting

confidence: 91%

“…Fig. 1a) 16 . These populations were selected according to the sorting scheme we developed 36,37 , which achieves the highest purity compared to other studies 17 and allows isolation of HSCs with intermediate potential (~30%) for improved resolution at the apex of the normal hematopoietic hierarchy 36 (see Methods).…”

Section: Accessible Tes Distinguish Primitive From Mature Cellsmentioning

confidence: 99%

“…This phenotypic heterogeneity relies on population-specific genetic architectures, where phenotypically distinct populations arise from the contribution of different sections of a shared genome 11,[13][14][15] . For instance, chromatin accessibility across hematopoietic populations reveals how DNA recognition sequences for CTCF contribute to the transition of dormant, low primed to activated, primed HSC and mediate changes to the three-dimensional genome organization 16 . In contrast, DNA recognition sequences of lineage-specific transcription regulators are uniquely accessible to serve as cis-regulatory elements promoting lineage-specific expression profiles across each mature population 16,17 .…”

Section: Introductionmentioning

confidence: 99%

“…For instance, chromatin accessibility across hematopoietic populations reveals how DNA recognition sequences for CTCF contribute to the transition of dormant, low primed to activated, primed HSC and mediate changes to the three-dimensional genome organization 16 . In contrast, DNA recognition sequences of lineage-specific transcription regulators are uniquely accessible to serve as cis-regulatory elements promoting lineage-specific expression profiles across each mature population 16,17 . Hence, characterizing the chromatin accessibility across hematopoietic populations identifies genetic determinants of phenotypic heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

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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 Tes As Docking Sites For Stem Factorssupporting

confidence: 91%

Section: Accessible Tes Distinguish Primitive From Mature Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

Nadorp

Grillo

Qamra

et al. 2021

Preprint

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“…Changes to focal chromatin interactions have been observed in the absence of higher-order chromatin changes 45,46 , and we hypothesized that this may be the case in PCa.…”

Section: Focal Chromatin Interactions Shifting Over Oncogenesismentioning

confidence: 97%

Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

Hawley

Zhou

Arlidge

et al. 2021

Preprint

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Prostate cancer is a heterogeneous disease whose progression is linked to genome instability 1. Despite large-scale tumour sequencing efforts, the impact of mutations on the genetic architecture in cancer remains ill-defined due to limited integration of genomics data across dimensions 2. We addressed this limitation by assessing the impact of structural variants on the chromatin states and the three-dimensional organization across benign and malignant primary prostate genomes. We find high concordance in the three-dimensional genome organization between malignant and benign prostate tissues, arguing for constraints to the three-dimensional genome of prostate tumours. Moreover, we identify structural variants as effectors of changes to focal chromatin interactions, guiding cis-regulatory element hijacking 2,3 that imposes opposing expression changes on genes found at antipodes of a rearrangement. This leads to the repression of tumour suppressor gene expression and up-regulation of oncogenes, such as at the TMPRSS2-ERG and PMEPA1-ZNF156 loci. Collectively, our results argue that cis-regulatory element hijacking by structural variants overshadows large-scale topological changes to alter gene regulation and promote oncogenesis.

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