Dynamic 3D chromosomal landscapes in acute leukemia

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Three-dimensional (3D) chromatin architectural changes can alter the integrity of topologically associated domains (TADs) and rewire specific enhancer-promoter interactions impacting gene expression. Recently, such alterations have been implicated in human disease, highlighting the need for a deeper understanding of their role. Here, we investigate the reorganization of chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) using primary human leukemia specimens and its dynamic responses to pharmacological agents. Systematic integration of matched <jats:italic>in situ</jats:italic> Hi-C, RNA-Seq and CTCF ChIP-Seq datasets revealed widespread changes in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD “fusion” event being associated with loss of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data show that small molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation reduce specific 3D interactions associated with transformation. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.</jats:p><jats:sec><jats:title>One Sentence Summary</jats:title><jats:p>3D chromatin alterations in T cell leukemia are accompanied by changes in insulation and oncogene expression and can be partially restored by targeted drug treatments.</jats:p></jats:sec>

A Tumor Suppressor Enhancer ofPTENin T-cell Development and Leukemia

“…1A, lower tracks), which has also been suggested to mark active enhancer regulatory elements (20,21). Finally, analyses of publicly available H3K27ac Hi-ChIP data in CUTLL1 T-ALL cells (19) revealed that, among the different interacting regions with the PTEN promoter, the interaction with the PE enhancer is the only one detected at FDR <1E-15 ( Fig. 1A, top).…”

“…1A, CTCF track), suggesting that cohesin-mediated loops might be responsible for this interaction (15)(16)(17)(18). In addition, GRO-seq analyses of T-ALL cells (19) uncovered bi-directional transcription from this region (Fig. 1A, lower tracks), which has also been suggested to mark active enhancer regulatory elements (20,21).…”

Cancer Is Associated with Alterations in the Three-Dimensional Organization of the Genome

“…In fact, only a small number of patient Hi-C datasets have been generated. For instance, Kloetgen et al have produced and studied Hi-C data for six primary T-cell acute lymphoblastic leukemia (T-ALL) patients [32], and Díaz et al have done so for one large B-cell lymphoma patient [33]. To conduct an independent validation of some of our results, we compared a list of 37 TADs that have been reported to undergo structural changes in the B-cells of lymphoma patients [33] to our normal consensus TADs; we observed that 78% (29/37) of these 37 TADs overlapped by at least 90% with our consensus TADs, but only 8% (3/37) overlapped with constitutive TADs, while the expectation based on their sizes is 27% (10/37).…”

Structural Variants as a Basis for Targeted Therapies in Hematological Malignancies

“…This promising study interrogating the disruption of long-distance interactions between enhancers and promoters might lead the way to new cancer treatment options targeting the 3D genome organization. Furthermore, it has been shown that a fusion of two TADs accompanied by an almost complete loss of CTCF binding at the boundary between these two TADs leads to an interaction between the MYC promoter and a distal super-enhancer in primary T-ALL samples as well as T-ALL cell lines (72). The increased looping events can be inhibited by using small molecule inhibitors against oncogenic signaling molecules or epigenetic modifiers (72).…”

“…Furthermore, it has been shown that a fusion of two TADs accompanied by an almost complete loss of CTCF binding at the boundary between these two TADs leads to an interaction between the MYC promoter and a distal super-enhancer in primary T-ALL samples as well as T-ALL cell lines (72). The increased looping events can be inhibited by using small molecule inhibitors against oncogenic signaling molecules or epigenetic modifiers (72). Another study reveals that a mutation within the EZH2 gene encoding a histone lysine methyltransferase and present among others in non-Hodgkin lymphomas leads to increased H3K27me3 as well as changes in the TAD structure resulting in intra-TAD gene silencing, which can be restored by pharmacological inhibition of the mutant EZH2 (73).…”