Deciphering the role of RNA in regulating CTCF's DNA binding affinity in leukemia cells.

Background: CTCF, a highly studied transcription factor, is essential for chromatin interaction maintenance. Several independent studies report that CTCF interacts with RNAs in vitro and in cells. Yet continuous debates about the authenticity of the RNA-binding affinity of CTCF and its biological role remain in large part due to limited research techniques available, such as CLIP-seq.

CTCF is selectively required for maintaining chromatin accessibility and gene expression in human erythropoiesis.

Background: CTCF is considered as the most essential transcription factor regulating chromatin architecture and gene expression. However, genome-wide impact of CTCF on erythropoiesis has not been extensively investigated.

Results: Using a state-of-the-art human erythroid progenitor cell model (HUDEP-2 and HEL cell lines), we systematically investigate the effects of acute CTCF loss by an auxin-inducible degron system on transcriptional programs, chromatin accessibility, CTCF genome occupancy, and genome architecture.

PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression.

Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo.

Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma.

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors.

Functional characterization of cooperating MGA mutations in RUNX1::RUNX1T1 acute myeloid leukemia.

MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in MGA have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with RUNX1::RUNX1T1, however, very little is known about the impact of these MGA alterations on normal hematopoiesis or disease progression. We show that representative MGA mutations identified in patient samples abolish protein-protein interactions and transcriptional activity.

Genomic and global gene expression profiling in pediatric and young adult acute leukemia with PICALM::MLLT10 Fusion.

MLLT10 fusion is a rare but recurrent genetic driver in acute leukemias. To better understand the genomic landscape of PICALM::MLLT10 (PM) positive acute leukemia, we performed genomic profiling and gene expression profiling in twenty PM-positive patients, including AML (n = 10), T-ALL/LLy (n = 8), Mixed-phenotype acute leukemia (MPAL), T/B (n = 1) and acute undifferentiated leukemia (AUL) (n = 1). Besides confirming the known activation of HOXA, differential gene expression analysis compared to hematopoietic stem cells demonstrated the enrichment of genes associated with cell proliferation-related pathways and relatively high expression of XPO1 in PM-AML and PM-T-ALL/LLy.

Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens.

Accumulating evidence indicates that HOXA9 dysregulation is necessary and sufficient for leukemic transformation and maintenance. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes. Here, we conduct dropout CRISPR screens against 229 HOXA9-bound peaks identified by ChIP-seq.

Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.

MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with however, very little is known about the impact of these alterations on normal hematopoiesis or disease progression. We show that representative mutations identified in patient samples abolish protein-protein interactions and transcriptional activity.

Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens.

Bromo- and extra-terminal domain inhibitors (BETi) have exhibited therapeutic activities in many cancers. However, the mechanisms controlling BETi response and resistance are not well understood. We conducted genome-wide loss-of-function CRISPR screens using BETi-treated KMT2A-rearranged (KMT2A-r) cell lines.

ZBTB18 restricts chromatin accessibility and prevents transcriptional adaptations that drive metastasis.

Metastases arise from rare cancer cells that successfully adapt to the diverse microenvironments encountered during dissemination through the bloodstream and colonization of distant tissues. How cancer cells acquire the ability to appropriately respond to microenvironmental stimuli remains largely unexplored. Here, we report an epigenetic pliancy mechanism that allows cancer cells to successfully metastasize.

The MLL3/4 complexes and MiDAC co-regulate H4K20ac to control a specific gene expression program.

The mitotic deacetylase complex MiDAC has recently been shown to play a vital physiological role in embryonic development and neurite outgrowth. However, how MiDAC functionally intersects with other chromatin-modifying regulators is poorly understood. Here, we describe a physical interaction between the histone H3K27 demethylase UTX, a complex-specific subunit of the enhancer-associated MLL3/4 complexes, and MiDAC.

Genomic profiling identifies genes and pathways dysregulated by HEY1-NCOA2 fusion and shines a light on mesenchymal chondrosarcoma tumorigenesis.

Mesenchymal chondrosarcoma is a rare, high-grade, primitive mesenchymal tumor. It accounts for around 2-10% of all chondrosarcomas and mainly affects adolescents and young adults. We previously described the HEY1-NCOA2 as a recurrent gene fusion in mesenchymal chondrosarcoma, an important breakthrough for characterizing this disease; however, little study had been done to characterize the fusion protein functionally, in large part due to a lack of suitable models for evaluating the impact of HEY1-NCOA2 expression in the appropriate cellular context.

PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands.

DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2, the glycosyltransferase OGT and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes.

CovidExpress: an interactive portal for intuitive investigation on SARS-CoV-2 related transcriptomes.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans could cause coronavirus disease 2019 (COVID-19). Since its first discovery in Dec 2019, SARS-CoV-2 has become a global pandemic and caused 3.3 million direct/indirect deaths (2021 May).

Promoter switching in response to changing environment and elevated expression of protein-coding genes overlapping at their 5' ends.

Despite the number of studies focused on sense-antisense transcription, the key question of whether such organization evolved as a regulator of gene expression or if this is only a byproduct of other regulatory processes has not been elucidated to date. In this study, protein-coding sense-antisense gene pairs were analyzed with a particular focus on pairs overlapping at their 5' ends. Analyses were performed in 73 human transcription start site libraries.

TET2 deficiency reprograms the germinal center B cell epigenome and silences genes linked to lymphomagenesis.

The TET2 DNA hydroxymethyltransferase is frequently disrupted by somatic mutations in diffuse large B cell lymphomas (DLBCLs), a tumor that originates from germinal center (GC) B cells. Here, we show that TET2 deficiency leads to DNA hypermethylation of regulatory elements in GC B cells, associated with silencing of the respective genes. This hypermethylation affects the binding of transcription factors including those involved in exit from the GC reaction and involves pathways such as B cell receptor, antigen presentation, CD40, and others.

Graph embedding and unsupervised learning predict genomic sub-compartments from HiC chromatin interaction data.

Chromatin interaction studies can reveal how the genome is organized into spatially confined sub-compartments in the nucleus. However, accurately identifying sub-compartments from chromatin interaction data remains a challenge in computational biology. Here, we present Sub-Compartment Identifier (SCI), an algorithm that uses graph embedding followed by unsupervised learning to predict sub-compartments using Hi-C chromatin interaction data.