Deciphering the Complexity of 3D Chromatin Organization Driving Lymphopoiesis and Lymphoid Malignancies

Scourzic, Laurianne; Salataj, Eralda; Apostolou, Effie

doi:10.3389/fimmu.2021.669881

Cited by 13 publications

(15 citation statements)

References 264 publications

(320 reference statements)

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“…We have left the discussions on the dynamics of enhancer–promoter looping in specific biological settings outside the scope of this review. Several recent articles have provided up-to-date perspectives in this regard for various systems, including lymphocyte development [ 250 , 251 ], heart development and disease [ 252 ], and cancer [ 253 ].…”

Section: Enhancer–promoter Communication In Three Dimensionsmentioning

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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Section: Enhancer–promoter Communication In Three Dimensionsmentioning

confidence: 99%

Transcriptional enhancers and their communication with gene promoters

Ray-Jones

Spivakov

2021

Cell. Mol. Life Sci.

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“…More importantly, a single miRNA can regulate very large sets of genes, thereby influencing almost every metabolic and regulatory pathway in individuals who are healthy as well asdisease 15,36–38 . A growing number of MiRNAs that target genes involved in the hematopoietic process are dysregulated in human leukemia 39–42 . In t(4;11) ALL, MLL‐AF4 activates aberrant expression of the oncogenic miR‐130b and miR‐128a; 43 in contrast, the tumor suppressor miR‐142‐3p, miR‐142‐3p, and miR‐205 target and downregulate MLL‐AF4 and AF4 44–46 …”

Section: Discussionmentioning

confidence: 99%

“…15,[36][37][38] A growing number of MiRNAs that target genes involved in the hematopoietic process are dysregulated in human leukemia. [39][40][41][42] In t(4;11) ALL, MLL-AF4 activates aberrant expression of the oncogenic miR-130b and miR-128a; 43 in contrast, the tumor suppressor miR-142-3p, miR-142-3p, and miR-205 target and downregulate MLL-AF4 and AF4. [44][45][46] The scaffold protein 14-3-3θ, a direct interactor of AF4 and MLL-AF4, acquires an opportunistic oncogenic role in t(4;11) leukemia.…”

Section: Discussionmentioning

confidence: 99%

“… 15 , 36 , 37 , 38 A growing number of MiRNAs that target genes involved in the hematopoietic process are dysregulated in human leukemia. 39 , 40 , 41 , 42 In t(4;11) ALL, MLL‐AF4 activates aberrant expression of the oncogenic miR‐130b and miR‐128a; 43 in contrast, the tumor suppressor miR‐142‐3p, miR‐142‐3p, and miR‐205 target and downregulate MLL‐AF4 and AF4. 44 , 45 , 46 …”

Section: Discussionmentioning

confidence: 99%

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MiR‐27a downregulates 14‐3‐3θ, RUNX1, AF4, and MLL‐AF4, crucial drivers of blast transformation in t(4;11) leukemia cells

Fioretti

Zanobio

Raia

et al. 2022

Cell Biochemistry & Function

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The chromosomal translocation t(4;11)(q21;q23), a hallmark of an aggressive form of acute lymphoblastic leukemia (ALL), encodes mixed‐lineage leukemia (MLL)‐AF4 oncogenic chimera that triggers aberrant transcription of genes involved in lymphocyte differentiation, including HOXA9 and MEIS1. The scaffold protein 14‐3‐3θ, which promotes the binding of MLL‐AF4 to the HOXA9 promoter, is a target of MiR‐27a, a tumor suppressor in different human leukemia cell types. We herein study the role of MiR‐27a in the pathogenesis of t(4;11) ALL. Reverse transcription quantitative PCR (qPCR) reveals that MiR‐27a and 14‐3‐3θ expression is inversely correlated in t(4;11) ALL cell lines; interestingly, MiR‐27a relative expression is significantly lower in patients affected by t(4;11) ALL than in patients affected by the less severe t(12;21) leukemia. In t(4;11) leukemia cells, ectopic expression of MiR‐27a decreases protein level of 14‐3‐3θ and of the key transcription factor RUNX1. We show for the first time that MiR‐27a also targets AF4 and MLL‐AF4; in agreement, MiR‐27a overexpression strongly reduces AF4 and MLL‐AF4 protein levels in RS4;11 cells. Consequent to AF4 and MLL‐AF4 downregulation, MiR‐27a overexpression negatively affects transcription of HOXA9 and MEIS1 in different t(4;11) leukemia cell lines. In agreement, we show through chromatin immunoprecipitation experiments that MiR‐27a overexpression impairs the binding of MLL‐AF4 to the HOXA9 promoter. Lastly, we found that MiR‐27a overexpression decreases viability, proliferation, and clonogenicity of t(4;11) cells, whereas it enhances their apoptotic rate. Overall, our study identifies the first microRNAthat strikes in one hit four crucial drivers of blast transformation in t(4;11) leukemia. Therefore, MiR‐27a emerges as a new promising therapeutic target for this aggressive and poorly curable form of leukemia.

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“…By forming longrange loops, they bring to proximity genes that may not be meant to interact with each other, thus interfering with the proper regulation of their expression. This deregulation in gene expression can contribute to the multiplicity of phenotypes observed in cancers (175)(176)(177). Apart from abnormal gene expression, mediated by high order looping, some cancer cells evade immune detection and clearance by upregulating the expression of the Programmed Cell Death Protein 1 and its ligand (PD1-PDL1) pathway.…”

Section: Satb1 In (Patho)physiologymentioning

confidence: 99%

3D Genome Organization as an Epigenetic Determinant of Transcription Regulation in T Cells

2022

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In the heart of innate and adaptive immunity lies the proper spatiotemporal development of several immune cell lineages. Multiple studies have highlighted the necessity of epigenetic and transcriptional regulation in cell lineage specification. This mode of regulation is mediated by transcription factors and chromatin remodelers, controlling developmentally essential gene sets. The core of transcription and epigenetic regulation is formulated by different epigenetic modifications determining gene expression. Apart from “classic” epigenetic modifications, 3D chromatin architecture is also purported to exert fundamental roles in gene regulation. Chromatin conformation both facilitates cell-specific factor binding at specified regions and is in turn modified as such, acting synergistically. The interplay between global and tissue-specific protein factors dictates the epigenetic landscape of T and innate lymphoid cell (ILC) lineages. The expression of global genome organizers such as CTCF, YY1, and the cohesin complexes, closely cooperate with tissue-specific factors to exert cell type-specific gene regulation. Special AT-rich binding protein 1 (SATB1) is an important tissue-specific genome organizer and regulator controlling both long- and short-range chromatin interactions. Recent indications point to SATB1’s cooperation with the aforementioned factors, linking global to tissue-specific gene regulation. Changes in 3D genome organization are of vital importance for proper cell development and function, while disruption of this mechanism can lead to severe immuno-developmental defects. Newly emerging data have inextricably linked chromatin architecture deregulation to tissue-specific pathophysiological phenotypes. The combination of these findings may shed light on the mechanisms behind pathological conditions.

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Deciphering the Complexity of 3D Chromatin Organization Driving Lymphopoiesis and Lymphoid Malignancies

Cited by 13 publications

References 264 publications

Transcriptional enhancers and their communication with gene promoters

Transcriptional enhancers and their communication with gene promoters

MiR‐27a downregulates 14‐3‐3θ, RUNX1, AF4, and MLL‐AF4, crucial drivers of blast transformation in t(4;11) leukemia cells

3D Genome Organization as an Epigenetic Determinant of Transcription Regulation in T Cells

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