GATA3-Controlled Nucleosome Eviction Drives MYC Enhancer Activity in T-cell Development and Leukemia

Abstract

Long-range enhancers govern the temporal and spatial control of gene expres s ion; however, the mechanisms that regulate enhancer activity during normal and malignant development remain poorly understood. Here, we demonstrate a role for aberrant chromatin accessibility in the regulation of MYC expression in T-cell lymphoblastic leukemia (T-ALL). Central to this process, the NOTCH1-MYC enhancer (N-Me), a long-range T cell-specifi c MYC enhancer, shows dynamic changes in chromatin accessibility during T-cell specifi cation and maturation and an aberrant high degree of chromatin accessibility in mouse and human T-ALL cells. Mechanistically, we demonstrate that GATA3driven nucleosome eviction dynamically modulates N-Me enhancer activity and is strictly required for NOTCH1-induced T-ALL initiation and maintenance. These results directly implicate aberrant regulation of chromatin accessibility at oncogenic enhancers as a mechanism of leukemic transformation. SIGNIFICANCE: MYC is a major effector of NOTCH1 oncogenic programs in T-ALL. Here, we show a major role for GATA3-mediated enhancer nucleosome eviction as a driver of MYC expression and leukemic transformation. These results support the role of aberrant chromatin accessibility and consequent oncogenic MYC enhancer activation in NOTCH1-induced T-ALL.

A Tumor Suppressor Enhancer ofPTENin T-cell Development and Leukemia

“…Here, we identify a previously unknown long-range enhancer region of PTEN located in a highly conserved intronic region of the neighboring RNLS gene, ~550Kb downstream of its transcriptional start site. We further prove that this enhancer region, named PE for PTEN enhancer, acts as a hub for a plethora of major We have previously demonstrated the importance of long-range regulatory sequences in T-ALL pathogenesis in vivo, as MYC expression is exquisitely dependent on the NOTCH1-driven N-Me MYC enhancer in T-cells (1,6). Indeed, enhancer deregulation is now considered to be a common mechanism contributing to cancer development (5).…”

“…Enhancers are distal DNA regulatory regions that act in cis, and in orientationindependent manner, to regulate gene expression through three-dimensional physical interaction with gene promoters (1)(2)(3)(4). In recent years, enhancer malfunction has been shown to play a key role in cancer (5).…”

Combinatorial ETS1-Dependent Control of Oncogenic NOTCH1 Enhancers in T-cell Leukemia

“…It is possible that GATA3 might act as a scaffold linking ETS1 to the NOTCH1 complex. GATA3 pioneering factor activity can facilitate nucleosome eviction at the N-ME to promote transcription factor binding (12). Thus, GATA3-driven chromatin remodeling might help other proteins "connect" ETS1 to the Notch complex.…”

“…In vertebrates, Notch1 directly induces MYC expression in T-cell progenitors and T-ALL cells through the T-cell-specific Notch-MYC enhancer (N-ME; refs. 10,11), which is selectively active and competent for Notch1-driven transcriptional activation through the pioneering activity of the chromatin remodeler GATA3 (12). Here, we hypothesized that Notch1collaborating transcription factors are required to drive gene expression programs that promote Notch-induced T-ALL but less so to maintain tissue homeostasis.…”

The role of noncoding mutations in blood cancers

“…Deletion of N-Me reduced thymic cellularity and mature T cell counts, but made knockout mice resistant to NOTCH1-induced T-ALL. Further analysis of this regulatory element has identified the role for GATA3-mediated nucleosomal eviction in its activation (Belver et al, 2019)…”