Article-Journal |

[23] Golcadomide: An Oral CELMoD Agent Targeting IKZF1/3 For Diffuse Large B-Cell Lymphoma

Wed, 01 Jan 2025 00:00:00 +0000

[22] O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer

Mon, 01 Jul 2024 00:00:00 +0000

CDK4/6 inhibitors (e.g., palbociclib) have revolutionized the treatment of hormone receptor-positive breast cancer. However, resistance inevitably emerges, leading to treatment failure. Understanding the mechanisms of this resistance is crucial for developing next-generation therapies.

In this study, we identified a novel mechanism of resistance involving the transcription factor MITF (Microphthalmia-associated Transcription Factor). We found that MITF is post-translationally modified by O-GlcNAcylation, a sugar modification that significantly enhances its stability and transcriptional activity.

Our deep dive revealed:

The Mechanism: High glucose metabolism in cancer cells drives O-GlcNAcylation of MITF.
The Consequence: Modified MITF promotes the expression of cell cycle regulators that bypass the CDK4/6 blockade.
Targeting the Pathway: Inhibiting the O-GlcNAc transferase (OGT) or downstream MITF targets re-sensitizes resistant cells to therapy.

This work links cancer metabolism (glucose usage) directly to drug resistance via a specific molecular switch, offering new targets for combination therapies.

[21] Matrin3 mediates differentiation through stabilizing chromatin loop-domain interactions and YY1 mediated enhancer-promoter interactions

Thu, 01 Feb 2024 00:00:00 +0000

[20] Mechanistic and kinetic insights into Transcription factor biology via acute protein depletion

Mon, 01 Jan 2024 00:00:00 +0000

[19] Identifying Quantitatively Differential Chromosomal Compartmentalization Changes and Their Biological Significance from Hi-C data using DARIC

Sun, 01 Jan 2023 00:00:00 +0000

Chromosomal compartments are key features of the 3D genome organization, segregating the genome into active (A) and inactive (B) spatial domains. Changes in these compartments are often associated with developmental transitions and disease states, such as cancer. However, systematically identifying and quantifying these changes has been a challenge.

We developed DARIC (Differential Analysis of Regulated In-Compartments), a computational method designed to identify statistically significant differential compartmentalization changes between biological conditions. Unlike traditional methods that rely on fixed thresholds or visual inspection, DARIC utilizes a rigorous statistical framework to detect compartment switches (e.g., A-to-B or B-to-A transitions) and subtle quantitative changes in compartment strength.

We applied DARIC to Hi-C data from leukemia cell lines and normal hematopoietic cells, revealing that compartment switching is not just a passive reflection of gene expression but can actively drive oncogenic programs. Specifically, we identified leukemia-specific compartment changes that facilitate the activation of key oncogenes and the repression of tumor suppressors.

This work provides a robust tool for the chromatin biology community to dissect the functional role of 3D genome reorganization in development and disease.

[18] MLL::AF9 degradation induces rapid changes in transcriptional elongation and subsequent loss of an active chromatin landscape

Wed, 02 Mar 2022 00:00:00 +0000

[17] Lysine methyltransferase Kmt2d regulates naive CD8+ T cell activation-induced survival

Sun, 02 Jan 2022 00:00:00 +0000

[16] A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

Tue, 01 Mar 2022 00:00:00 +0000

[15] Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells

Sat, 01 Jan 2022 00:00:00 +0000

The fetal-to-adult hemoglobin switch is a classic model of developmental gene regulation, controlled by the repressor BCL11A. However, distinguishing the primary effects of BCL11A removal from secondary, downstream consequences has been difficult with traditional genetic knockout methods, which take days to deplete the protein.

In this study, we employed PROTAC (Proteolysis Targeting Chimera) technology to degrade the BCL11A protein within minutes in human erythroid cells. This acute depletion allowed us to perform a high-temporal-resolution analysis of the molecular events following repressor loss.

We discovered that:

Rapid Derepression: Fetal hemoglobin (HbF) genes are derepressed within hours of BCL11A degradation.
Transcription First: Transcriptional activation occurs before significant changes in chromatin accessibility or compartment switching, challenging the view that chromatin opening is always the prerequisite for transcription.
Proteome Dynamics: We mapped the global proteome changes, identifying specific co-repressors that dissociate from the globin locus upon BCL11A degradation.

This “deep dive” into the kinetics of gene regulation highlights the power of chemical biology tools in dissecting complex biological mechanisms.

[14] Transcription factor competition at the γ-globin promoters controls hemoglobin switching

Thu, 01 Apr 2021 00:00:00 +0000

Hemoglobin switching involves the silencing of fetal gamma-globin genes and the activation of adult beta-globin genes. While BCL11A is known as the master repressor, the precise molecular mechanism of its action at the promoter level remained elusive.

By integrating high-resolution genomic data with thermodynamic modeling, we demonstrated a transcription factor competition model. We found that BCL11A does not merely sit on the DNA to block access; it actively competes with transcriptional activators (such as NF-Y and LRF) for binding to overlapping motifs at the CCAAT box region of the gamma-globin promoters.

Key findings include:

Direct Competition: The binding of BCL11A mutually excludes the binding of ubiquitous activators.
Thermodynamic Control: The outcome of the switch is determined by the relative concentrations and binding affinities of these competing factors.
Therapeutic Implications: Disrupting the BCL11A binding site tips the balance in favor of activators, leading to HbF re-induction—a strategy now utilized in gene therapies for Sickle Cell Disease and Beta-Thalassemia.

This study provides a mechanistic framework for understanding how repressor-activator interplay dictates cell fate decisions.

[13] Mapping the evolving landscape of super-enhancers during cell differentiation

Sat, 02 Jan 2021 00:00:00 +0000

Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive high-level expression of genes defining cell identity. While SEs have been cataloged in many static cell types, understanding how they evolve during dynamic processes like differentiation is critical.

In this study, we performed a comprehensive mapping of SEs during hematopoietic differentiation. We developed computational approaches to track “SE constellations”—groups of enhancer constituents that merge, split, or shift during development.

Our findings shed light on:

Dynamic Remodeling: SEs are highly dynamic, with components being decommissioned or engaging new partners to shift gene expression programs.
Hierarchical Regulation: We identified “hub” enhancers within SEs that are essential for the integrity of the entire regulatory domain.
Disease Variants: Many disease-associated genetic variants (GWAS hits) cluster within these dynamic SE regions, suggesting a mechanism by which they perturb developmental trajectories.

This landscape provides a resource for understanding the regulatory logic governing cell fate decisions.

[12] Inner nuclear protein Matrin-3 coordinates cell differentiation by stabilizing chromatin architecture

Fri, 01 Jan 2021 00:00:00 +0000

[11] BAP1 is a haploinsufficient tumor suppressor linking chronic pancreatitis to pancreatic cancer in mice

Wed, 01 Jan 2020 00:00:00 +0000

[10] Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer

Sun, 01 Dec 2019 00:00:00 +0000

[9] miR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer

Tue, 01 Jan 2019 00:00:00 +0000

[8] Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors

Thu, 01 Mar 2018 00:00:00 +0000

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers. We investigated the role of KDM6A, a histone demethylase (an epigenetic eraser) that is frequently mutated in various cancers.

In this study, we discovered a surprising mechanism:

Tumor Suppressor: KDM6A acts as a tumor suppressor in the pancreas.
Super-Enhancer Activation: Its loss leads to the aberrant activation (“opening”) of super-enhancers that drive a squamous-like, aggressive identity.
Therapeutic Vulnerability: Because this tumor subtype relies heavily on these super-enhancers (driven by BET proteins), these cancers are exceptionally sensitive to BET inhibitors (drugs that disrupt super-enhancers).

This work not only defined a specific molecular subtype of pancreatic cancer but also provided a direct therapeutic roadmap for targeting it—a prime example of “epigenetic therapy.”

[7] Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance

Tue, 02 Jan 2018 00:00:00 +0000

[6] DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer

Mon, 01 Jan 2018 00:00:00 +0000

[5] Predicting CTCF-mediated chromatin interactions by integrating genomic and epigenomic features

Sat, 01 Sep 2018 00:00:00 +0000

CTCF (CCCTC-binding factor) is often called the “master weaver” of the genome, creating the 3D loops and domains that organize our DNA. While there are thousands of CTCF binding sites, only a fraction of them form loops. Predicting which pairs of CTCF sites interact is a major challenge in understanding 3D genome architecture.

We addressed this by developing a predictive model that integrates:

Motif Orientation: The convergent orientation of CTCF motifs is a strong predictor, but not sufficient on its own.
Epigenomic Features: We incorporated histone modification data, chromatin accessibility, and co-factor binding.
Genomic Distance: The distance between sites is a key constraint.

Our model accurately predicts chromatin loops in varying cell types and highlighted the importance of RNA Polymerase II and Cohesin in stabilizing these structures. This work represented a step forward in “in silico” folding of the genome, allowing us to predict the impact of mutations on 3D structure and gene regulation.

[4] dbVar structural variant cluster set for data analysis and variant comparison

Sun, 01 Jan 2017 00:00:00 +0000

[3] Lysine-specific histone demethylases in normal and malignant hematopoiesis

Thu, 01 Sep 2016 00:00:00 +0000

[2] Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis

Fri, 01 Jan 2016 00:00:00 +0000

[1] Highly stable and AC electric field-activated electrorheological fluid based on mesoporous silica-coated graphene nanosheets

Tue, 01 Jan 2013 00:00:00 +0000