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JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE251729 | GEO | 2025/06/04

REPOSITORIES: GEO

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JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells [RNA-seq]

Project description:Dysregulation of transcriptional programs that establish and maintain specific cell identities can lead to various diseases, especially cancer. Acute myeloid leukemia (AML) is an extremely heterogeneous malignancy with frequent genetic mutations such as transcription factors (TFs) and epigenetic factors, resulting in gene dysregulation, differentiation blockade and aberrant proliferation of immature clonal myeloid cells. Various AML subtypes usually involve in distinct genetic alterations, and most studies and therapeutic drugs are focused on specific AML genetic abnormalities. However, whether these seemingly different AML subtypes share a universal transcriptional programs and regulation mechanism is not clear. Identification of such program could help finding of common vulnerabilities and thus future therapeutics against multiple AML subtypes. In this study, we set out to elucidate the underlying mechanism that explains the general dependency towards JMJD1C by AML with different genetic backgrounds. Towards this goal, we first identify RUNX1 as a transcription factor that recruits JMJD1C to chromatin in multiple types of leukemia. Second, we show that JMJD1C directly interacts with RUNX1 at the N-terminus and they co-regulate a set of genes required by leukemic cells. Finally, we found that the N-terminus of JMJD1C could form liquid-like biomolecular RUNX1-containing condensates that are independent of its enzymatic activity, to mediate promoter-enhancer interactions to activate downstream gene expression.

2025-06-04 | GSE251728 | GEO

JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells [ChIP-seq]

2025-06-04 | GSE251726 | GEO

JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells [4C-seq]

2025-06-04 | GSE251725 | GEO

JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells

Project description:JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells

| PRJNA1055129 | ENA

JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells [ChIP-seq]

Project description:JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells [ChIP-seq]

| PRJNA1055125 | ENA

JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells [RNA-seq]

Project description:JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells [RNA-seq]

| PRJNA1055138 | ENA

JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells [4C-seq]

Project description:JMJD1C facilitates long distance genomic interactions by promoting condensates formation of key leukemic transcription factors in multiple AML cells [4C-seq]

| PRJNA1055123 | ENA

Modulators of histone demethylase JMJD1C selectively target leukemic stem cells.

Project description:Leukemic stem cells (LSCs) comprise a very rare cell population that results in the development of acute myeloid leukemia. The selective targeting of drivers in LSCs with small molecule inhibitors holds promise for treatment of acute myeloid leukemia. Recently, we reported the identification of inhibitors of the histone lysine demethylase JMJD1C that preferentially kill MLL rearranged acute leukemia cells. Here, we report the identification of jumonji domain modulator #7 (JDM-7). Surface plasmon resonance analysis showed that JDM-7 binds to JMJD1C and its family homolog JMJD1B. JDM-7 did not significantly suppress cell proliferation in liquid cell culture at higher doses, although it led to a significant decrease in semi-solid colony formation experiments at lower concentrations. Moreover, low doses of JDM-7 did not suppress the proliferation of erythroid progenitor cells. We identified that JDM-7 downregulates the LSC self-renewal gene HOXA9 in leukemia cells. We further found that the structure of JDM-7 is similar to that of tadalafil, a drug approved by the US Food and Drug Administration. Molecular docking and surface plasmon resonance analysis showed that tadalafil binds to JMJD1C. Moreover, similar to JDM-7, tadalafil suppressed colony formation of leukemia cells in semi-solid cell culture at a concentration that did not affect primary umbilical cord blood cells. In summary, we have identified JDM-7 and tadalafil as potential JMJD1C modulators that selectively inhibit the growth of LSCs.

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Long-distance association of topological boundaries through nuclear condensates.

Project description:The eukaryotic genome is partitioned into distinct topological domains separated by boundary elements. Emerging data support the concept that several well-established nuclear compartments are ribonucleoprotein condensates assembled through the physical process of phase separation. Here, based on our demonstration that chemical disruption of nuclear condensate assembly weakens the insulation properties of a specific subset (∼20%) of topologically associated domain (TAD) boundaries, we report that the disrupted boundaries are characterized by a high level of transcription and striking spatial clustering. These topological boundary regions tend to be spatially associated, even interchromosomally, segregate with nuclear speckles, and harbor a specific subset of "housekeeping" genes widely expressed in diverse cell types. These observations reveal a previously unappreciated mode of genome organization mediated by conserved boundary elements harboring highly and widely expressed transcription units and associated transcriptional condensates.

| S-EPMC9371644 | biostudies-literature

Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates.

Project description:The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells. The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2, resulting in conversion of Bcl-2 from a survival to killer. As Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy, targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer therapeutics. Here, we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway. In vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer (TNBC) and MCF-7/LCC2 tamoxifen-resistant breast cancer (TAMR) in a Nur77-dependent manner. Mechanistic studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria, resulting in mitochondria-related apoptosis. Interestingly, XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 condensates. Together, our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

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