ZNF143 mediates CTCF-bound promoter–enhancer loops required for murine hematopoietic stem and progenitor cell function

Zhou, Qiling; Yu, Miao; Tirado-Magallanes, Roberto; Li, Bin; Kong, Lingshi; Guo, Mingrui; Tan, Zhichao; Lee, Sanghoon; Chai, Li; Numata, Akihiko; Benoukraf, Touati; Fullwood, Melissa J.; Osato, Motomi; Ren, Bing; Tenen, Daniel G.

doi:10.1038/s41467-020-20282-1

Cited by 53 publications

(65 citation statements)

References 66 publications

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“…Of note, changes in chromatin accessibility regulates transcription of ALKBH5 , an important m 6 A demethylase required for maintaining leukemia stem cells (LSCs) function 72 . Due to the fact that chromatin status, such as histone modifications and chromatin interactions, plays important role in hematopoiesis 73,74 , another aspect to consider is that the regulation of ADAR2 expression through dynamic changes of chromatin status. In sum, our findings shed new light on future studies of dysregulated ADAR2 transcription and expression as well as their RNA editing-dependent or independent biological implications in multiple diseases including cancers.…”

Section: Discussionmentioning

confidence: 99%

ADAR2-repressed RNA editing: a novel mechanism contributing to t (8:21) AML leukemogenesis

Guo

Chan

et al. 2021

Preprint

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In the past decade, adenosine to inosine (A-to-I) RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes ADAR1 and ADAR2, has been shown to contribute to the development and progression of multiple cancers; however, very little is known about its role in acute myeloid leukemia (AML) - the second most common type of leukemia making up 31% of all adult leukemia cases. Here, we found that ADAR2, but not ADAR1 and ADAR3, is specifically downregulated in core binding factor (CBF) AML with t(8;21) or inv(16). In t(8;21) AML, RUNX1-driven transcription of ADAR2 transcripts was found to be repressed by the RUNX1-ETO fusion protein. Forced overexpression of two ADAR2-regulated RNA editing targets COPA and COG3 indeed inhibits clonogenic growth of human t(8;21) AML cells. Further in vivo animal studies confirmed that ADAR2 could suppress leukemogenesis of t(8;21) AML through its RNA binding and editing capabilities. Our results suggest a novel RNA editing-mediated mechanism leading to t(8,12) AML.

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Section: Discussionmentioning

confidence: 99%

ADAR2-repressed RNA editing: a novel mechanism contributing to t (8:21) AML leukemogenesis

Guo

Chan

et al. 2021

Preprint

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“…Meanwhile, ZNF143 binds to promoters globally [367] and was found at the anchors of many lineage-specific enhancer-promoter loops in human and mouse cells [362][363][364]368]. Unlike CTCF and cohesin, long-term depletion of YY1 or ZNF143 in mammalian cells causes a significant reduction of enhancer-promoter loops, coupled with substantial changes in gene expression [295,368,369] (although short-term YY1 depletion has only a modest effect on both [350]).…”

Section: Yy1 and Znf143mentioning

confidence: 99%

“…YY1 does not seem to co-localise with CTCF [365] and instead has been proposed to associate with cohesin independently, in a manner analogous to CTCF itself [295]. In contrast, ZNF143 co-localises with both CTCF and cohesin [369], and it has recently been shown that depletion of ZNF143 disrupts CTCF-mediated enhancer-promoter looping [368].…”

Section: Yy1 and Znf143mentioning

confidence: 99%

Transcriptional enhancers and their communication with gene promoters

Ray-Jones

Spivakov

2021

Cell. Mol. Life Sci.

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Transcriptional enhancers play a key role in the initiation and maintenance of gene expression programmes, particularly in metazoa. How these elements control their target genes in the right place and time is one of the most pertinent questions in functional genomics, with wide implications for most areas of biology. Here, we synthesise classic and recent evidence on the regulatory logic of enhancers, including the principles of enhancer organisation, factors that facilitate and delimit enhancer–promoter communication, and the joint effects of multiple enhancers. We show how modern approaches building on classic insights have begun to unravel the complexity of enhancer–promoter relationships, paving the way towards a quantitative understanding of gene control.

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“…While TEAD4 is known to contribute to drive embryonic cell commitment to blood cells 46 , GATA1, HIF1A and epigenetic enzymes SETB1, EZH2 and HDAC2 regulate HSCs self-renewal and/or differentiation 47–51 . Instead, ZNF143 and SMC3 bind to anchors of chromatin interactions to regulate the three-dimensional genome organisation, in collaboration with CTCF 38,52,53 . ZNF143 and SMC3 cistromes enrich over LTR41B elements with CTCF and known CTCF interactors (SMC1A, RAD21, CHD8 (q≤3.22e-34, OR≤9.36) (Suppl.…”

Section: Resultsmentioning

confidence: 99%

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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ZNF143 mediates CTCF-bound promoter–enhancer loops required for murine hematopoietic stem and progenitor cell function

Cited by 53 publications

References 66 publications

ADAR2-repressed RNA editing: a novel mechanism contributing to t (8:21) AML leukemogenesis

ADAR2-repressed RNA editing: a novel mechanism contributing to t (8:21) AML leukemogenesis

Transcriptional enhancers and their communication with gene promoters

Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

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