<link>https://ykai16.github.io/</link></image><item><title>[24] Development of a novel Ikaros/Aiolos transcriptional signature and correlation with patient response in multiple myeloma patients treated with CELMoDs</h1> <article> <h1>[24] Development of a novel Ikaros/Aiolos transcriptional signature and correlation with patient response in multiple myeloma patients treated with CELMoDs</h1> <p>Wed, 08 Apr 2026 00:00:00 +0000</p> <p>Multiple myeloma (MM) is a neoplasm characterized by the clonal proliferation of malignant plasma cells in the bone marrow. CELMoD™ agents—including iberdomide (IBER) and mezigdomide (MEZI)—modulate Cereblon to induce the degradation of the hematologic transcription factors Ikaros (Ik) and Aiolos (Ai), exerting anti-proliferative and pro-apoptotic effects on MM cells. While Ik/Ai protein degradation can be semi-quantified by immunohistochemistry (IHC), clinical responses are not always correlated with IHC readouts, motivating a more quantitative genomic approach.</p> <p>We performed <strong>CUT&RUN and ChIP-seq</strong> on the H929 MM cell line to map Ik binding targets genome-wide. By intersecting these targets with differential expression analysis (DESeq2) across multiple CELMoD treatments (LEN, POM, MEZI, IBER) at multiple timepoints, we compiled a high-confidence <strong>Ik regulon</strong> consisting of 115 up-regulated and 95 down-regulated target genes.</p> <p><strong>Gene Set Variation Analysis (GSVA)</strong> was then applied to this regulon to derive a sample-level <strong>Ik activity score</strong>. Key findings include:</p> <ul> <li><strong>On-treatment decrease</strong>: RNA-seq paired samples from MEZI-treated (N=7) and IBER-treated (N=41) patients showed significantly lower Ik activity scores at cycle 2 day 15 compared to screening.</li> <li><strong>Association with survival</strong>: Using an optimal cutpoint, greater on-treatment reduction in Ik activity score was significantly associated with longer <strong>progression-free survival (PFS)</strong> in IBER-treated patients.</li> <li><strong>Concordance with IHC</strong>: The RNA-seq based score showed significant agreement with IHC-based Ik degradation scores in a validation cohort (N=22), supporting its use as a complementary or standalone biomarker.</li> </ul> <p>This work establishes a robust transcriptomic framework for monitoring Ik/Ai target engagement and predicting clinical outcomes in MM patients receiving CELMoD therapy.</p> </article> <article> <h1>[23] Golcadomide: An Oral CELMoD Agent Targeting IKZF1/3 For Diffuse Large B-Cell Lymphoma</h1> <p>Wed, 01 Jan 2025 00:00:00 +0000</p> </article> <article> <h1>[22] O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer</h1> <p>Mon, 01 Jul 2024 00:00:00 +0000</p> <p>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.</p> <p>In this study, we identified a novel mechanism of resistance involving the transcription factor <strong>MITF</strong> (Microphthalmia-associated Transcription Factor). We found that MITF is post-translationally modified by <strong>O-GlcNAcylation</strong>, a sugar modification that significantly enhances its stability and transcriptional activity.</p> <p>Our deep dive revealed:</p> <ul> <li><strong>The Mechanism</strong>: High glucose metabolism in cancer cells drives O-GlcNAcylation of MITF.</li> <li><strong>The Consequence</strong>: Modified MITF promotes the expression of cell cycle regulators that bypass the CDK4/6 blockade.</li> <li><strong>Targeting the Pathway</strong>: Inhibiting the O-GlcNAc transferase (OGT) or downstream MITF targets re-sensitizes resistant cells to therapy.</li> </ul> <p>This work links cancer metabolism (glucose usage) directly to drug resistance via a specific molecular switch, offering new targets for combination therapies.</p> </article> <article> <h1>[21] Matrin3 mediates differentiation through stabilizing chromatin loop-domain interactions and YY1 mediated enhancer-promoter interactions</h1> <p>Thu, 01 Feb 2024 00:00:00 +0000</p> </article> <article> <h1>[20] Mechanistic and kinetic insights into Transcription factor biology via acute protein depletion</h1> <p>Mon, 01 Jan 2024 00:00:00 +0000</p> </article> <article> <h1>[19] Identifying Quantitatively Differential Chromosomal Compartmentalization Changes and Their Biological Significance from Hi-C data using DARIC</h1> <p>Sun, 01 Jan 2023 00:00:00 +0000</p> <p>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.</p> <p>We developed <strong>DARIC</strong> (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.</p> <p>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.</p> <p>This work provides a robust tool for the chromatin biology community to dissect the functional role of 3D genome reorganization in development and disease.</p> </article> <article> <h1>[18] MLL::AF9 degradation induces rapid changes in transcriptional elongation and subsequent loss of an active chromatin landscape</h1> <p>Wed, 02 Mar 2022 00:00:00 +0000</p> </article> <article> <h1>[17] Lysine methyltransferase Kmt2d regulates naive CD8+ T cell activation-induced survival</h1> <p>Sun, 02 Jan 2022 00:00:00 +0000</p> </article> <article> <h1>[16] A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia</h1> <p>Tue, 01 Mar 2022 00:00:00 +0000</p> </article> <article> <h1>[15] Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells</h1> <p>Sat, 01 Jan 2022 00:00:00 +0000</p> <p>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.</p> <p>In this study, we employed <strong>PROTAC (Proteolysis Targeting Chimera)</strong> 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.</p> <p>We discovered that:</p> <ol> <li><strong>Rapid Derepression</strong>: Fetal hemoglobin (HbF) genes are derepressed within hours of BCL11A degradation.</li> <li><strong>Transcription First</strong>: Transcriptional activation occurs <em>before</em> significant changes in chromatin accessibility or compartment switching, challenging the view that chromatin opening is always the prerequisite for transcription.</li> <li><strong>Proteome Dynamics</strong>: We mapped the global proteome changes, identifying specific co-repressors that dissociate from the globin locus upon BCL11A degradation.</li> </ol> <p>This “deep dive” into the kinetics of gene regulation highlights the power of chemical biology tools in dissecting complex biological mechanisms.</p> </article> <article> <h1>[14] Transcription factor competition at the γ-globin promoters controls hemoglobin switching</h1> <p>Thu, 01 Apr 2021 00:00:00 +0000</p> <p>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.</p> <p>By integrating high-resolution genomic data with thermodynamic modeling, we demonstrated a <strong>transcription factor competition model</strong>. 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.</p> <p>Key findings include:</p> <ul> <li><strong>Direct Competition</strong>: The binding of BCL11A mutually excludes the binding of ubiquitous activators.</li> <li><strong>Thermodynamic Control</strong>: The outcome of the switch is determined by the relative concentrations and binding affinities of these competing factors.</li> <li><strong>Therapeutic Implications</strong>: 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.</li> </ul> <p>This study provides a mechanistic framework for understanding how repressor-activator interplay dictates cell fate decisions.</p> </article> <article> <h1>[13] Mapping the evolving landscape of super-enhancers during cell differentiation</h1> <p>Sat, 02 Jan 2021 00:00:00 +0000</p> <p>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.</p> <p>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.</p> <p>Our findings shed light on:</p> <ul> <li><strong>Dynamic Remodeling</strong>: SEs are highly dynamic, with components being decommissioned or engaging new partners to shift gene expression programs.</li> <li><strong>Hierarchical Regulation</strong>: We identified “hub” enhancers within SEs that are essential for the integrity of the entire regulatory domain.</li> <li><strong>Disease Variants</strong>: Many disease-associated genetic variants (GWAS hits) cluster within these dynamic SE regions, suggesting a mechanism by which they perturb developmental trajectories.</li> </ul> <p>This landscape provides a resource for understanding the regulatory logic governing cell fate decisions.</p> </article> <article> <h1>[12] Inner nuclear protein Matrin-3 coordinates cell differentiation by stabilizing chromatin architecture</h1> <p>Fri, 01 Jan 2021 00:00:00 +0000</p> </article> <article> <h1>[11] BAP1 is a haploinsufficient tumor suppressor linking chronic pancreatitis to pancreatic cancer in mice</h1> <p>Wed, 01 Jan 2020 00:00:00 +0000</p> </article> <article> <h1>[10] Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer</h1> <p>Sun, 01 Dec 2019 00:00:00 +0000</p> </article> <article> <h1>[9] miR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer</h1> <p>Tue, 01 Jan 2019 00:00:00 +0000</p> </article> <article> <h1>[8] Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors</h1> <p>Thu, 01 Mar 2018 00:00:00 +0000</p> <p>Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers. We investigated the role of <strong>KDM6A</strong>, a histone demethylase (an epigenetic eraser) that is frequently mutated in various cancers.</p> <p>In this study, we discovered a surprising mechanism:</p> <ul> <li><strong>Tumor Suppressor</strong>: KDM6A acts as a tumor suppressor in the pancreas.</li> <li><strong>Super-Enhancer Activation</strong>: Its loss leads to the aberrant activation (“opening”) of super-enhancers that drive a squamous-like, aggressive identity.</li> <li><strong>Therapeutic Vulnerability</strong>: Because this tumor subtype relies heavily on these super-enhancers (driven by BET proteins), these cancers are exceptionally sensitive to <strong>BET inhibitors</strong> (drugs that disrupt super-enhancers).</li> </ul> <p>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.”</p> </article> <article> <h1>[7] Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance</h1> <p>Tue, 02 Jan 2018 00:00:00 +0000</p> </article> <article> <h1>[6] DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer</h1> <p>Mon, 01 Jan 2018 00:00:00 +0000</p> </article> <article> <h1>[5] Predicting CTCF-mediated chromatin interactions by integrating genomic and epigenomic features</h1> <p>Sat, 01 Sep 2018 00:00:00 +0000</p> <p>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.</p> <p>We addressed this by developing a predictive model that integrates:</p> <ol> <li><strong>Motif Orientation</strong>: The convergent orientation of CTCF motifs is a strong predictor, but not sufficient on its own.</li> <li><strong>Epigenomic Features</strong>: We incorporated histone modification data, chromatin accessibility, and co-factor binding.</li> <li><strong>Genomic Distance</strong>: The distance between sites is a key constraint.</li> </ol> <p>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.</p> </article> <article> <h1>[4] dbVar structural variant cluster set for data analysis and variant comparison</h1> <p>Sun, 01 Jan 2017 00:00:00 +0000</p> </article> <article> <h1>[3] Lysine-specific histone demethylases in normal and malignant hematopoiesis</h1> <p>Thu, 01 Sep 2016 00:00:00 +0000</p> </article> <article> <h1>[2] Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis</h1> <p>Fri, 01 Jan 2016 00:00:00 +0000</p> </article> <article> <h1>[1] Highly stable and AC electric field-activated electrorheological fluid based on mesoporous silica-coated graphene nanosheets</h1> <p>Tue, 01 Jan 2013 00:00:00 +0000</p> </article> <article> <h1>[25] DISSECTING THE MOLECULAR BASIS OF POTENT HBF INDUCTION BY BMS-986470: A MECHANISTIC STUDY OF ZBTB7A/WIZ DUAL DEGRADATION</h1> <p>Thu, 11 Jun 2026 00:00:00 +0000</p> <p>Sickle cell disease (SCD) remains a major global health burden with limited therapeutic options. Reactivation of fetal hemoglobin (HbF) is clinically validated to mitigate disease severity. <strong>BMS-986470</strong> is a first-in-class, orally bioavailable cereblon E3 ligase modulator (CELMoD™) that selectively degrades <strong>ZBTB7A</strong> and <strong>WIZ</strong>—two transcriptional repressors of the γ-globin genes previously considered undruggable—resulting in robust HbF induction and an erythroid program shift from adult β-globin toward fetal γ-globin expression. BMS-986470 is currently under clinical investigation (NCT06481306).</p> <h2 id="aims">Aims</h2> <p>We delineated the molecular mechanisms underlying BMS-986470–mediated HbF induction, with a focus on developing a better understanding of the contributions of ZBTB7A and WIZ degradation.</p> <h2 id="results">Results</h2> <p><strong>Genome-wide CRISPR screen.</strong> To compare the HbF-repressing capacity of ZBTB7A and WIZ, we performed an unbiased, phenotypic, genome-wide CRISPR-Cas9 screen in HUDEP-2 cells. Differential sgRNA enrichment/depletion between HbF-high and HbF-low populations provided a quantitative readout per gene. The screen recovered established HbF repressors (ZBTB7A, BCL11A, ZNF410, WIZ, CHD4), validating the approach. Notably, ZBTB7A-targeting sgRNAs were more enriched in HbF-high cells than WIZ-targeting sgRNAs, indicating stronger repression by ZBTB7A. Intriguingly, HBB emerged as the top-ranked HbF repressor genome-wide, consistent with reports that HBB promoter disruption facilitates fetal globin reactivation.</p> <p><strong>CRISPR knockout lines.</strong> We generated single and dual knockouts (KOs) of ZBTB7A/WIZ in HUDEP-2 cells. Immunoblotting showed greater γ-globin (HBG1/2) induction in ZBTB7A KO versus WIZ KO cells. The double KO further increased HBG1/2 and HbF tetramers while reducing adult β-globin (HBB) compared with either single KO, supporting a dominant role for ZBTB7A in fetal globin silencing.</p> <p><strong>Chromatin architecture by Micro-C.</strong> BMS-986470 induced a pronounced looping switch—reduced LCR–HBB contacts and increased LCR–HBG contacts—at the β-globin locus. Micro-C in KO lines showed that both ZBTB7A and WIZ loss disrupt LCR–HBB contacts; however, ZBTB7A KO produced a substantially stronger gain in LCR–HBG looping than WIZ KO. These findings implicate ZBTB7A as the stronger mediator of LCR-driven promoter competition and explain why dual degradation by BMS-986470 leads to a robust adult-to-fetal globin chromatin and transcriptional switch.</p> <h2 id="summary">Summary</h2> <p>We delineated the transcriptional and chromatin-level mechanisms of HbF regulation and established a functional hierarchy between ZBTB7A and WIZ. These findings provide mechanistic insights into the therapeutic potential of BMS-986470 for SCD treatment.</p> <p>This work was presented at the <strong>European Hematology Association (EHA) Annual Congress 2026</strong> in Stockholm, Sweden (June 2026).</p> </article> <article> <h1>I presented our work on HbF induction by BMS-986470 at EHA 2026 in Stockholm, Sweden.</h1> <p>Thu, 11 Jun 2026 00:00:00 +0000</p> <p>Excited to share that I presented our work on HbF induction by <strong>BMS-986470</strong>, a novel CELMoD agent for sickle cell disease, at the <strong>European Hematology Association (EHA) Annual Congress 2026</strong> in Stockholm, Sweden.</p> <p>Read the full story .</p> </article> <article> <h1>Our multi-omics study revealing an RNA-seq Ikaros/Aiolos signature for CELMoD response in multiple myeloma is accepted at AACR 2026!</h1> <p>Wed, 08 Apr 2026 00:00:00 +0000</p> <p>Excited to share that our abstract on a novel <strong>Ikaros/Aiolos transcriptional signature</strong> in multiple myeloma has been accepted and will be presented at the <strong>AACR Annual Meeting 2026</strong> (April 17–22, San Diego, CA)!</p> <p>Our work presents an RNA-seq based Ik/Ai activity score derived from preclinical genomic data and validates its association with patient response in CELMoD-treated multiple myeloma patients.</p> <p>Read the full story .</p> </article> <article> <h1>Introducing ContextMap: Session Intelligence for Claude Code</h1> <p>Sat, 21 Feb 2026 00:00:00 +0000</p> <p>Have you ever found yourself in an hours-long architectural refactoring session with Claude Code, only to pause and think: <em>“Wait, what did I actually modify three steps ago? Why did we go down this path again?”</em></p> <p>Today, I’m thrilled to introduce <strong> </strong>, a tool specifically designed to solve this exact problem.</p> <h2 id="the-problem-with-continuous-coding">The Problem with Continuous Coding</h2> <p>When interacting with AI coding assistants like Claude Code, your terminal becomes a massive, scrolling transcript of intents, failures, explorations, and successes. As projects grow in complexity—from standard web apps to computational biology foundation models—it’s incredibly easy to lose the overarching “arc” of what you’ve accomplished.</p> <p>By the end of the day or when you open your laptop the next morning, you’ve forgotten the sequence of critical project decisions. You end up having to re-read your commit logs or scroll endlessly through your terminal history.</p> <h2 id="enter-contextmap-your-projects-memory">Enter ContextMap: Your Project’s Memory</h2> <p><strong>ContextMap</strong> acts as your project’s memory. After you finish a coding session, it automatically analyzes the Claude Code transcripts to map out the evolution of your work. It synthesizes a beautiful, self-contained HTML report that reconstructs your journey—with emphasis on how each prompt <em>evolved</em> from the others.</p> <h3 id="key-features">Key Features</h3> <ul> <li><strong>Timeline Reconstruction:</strong> See every step of your project’s evolution displayed as a logical, chronological timeline.</li> <li><strong>Decisions & Triggers:</strong> Understand <em>why</em> you shifted focus (e.g., <em>“OOM crash during training → reconsidered our tokenization strategy”</em>).</li> <li><strong>Where We Left Off:</strong> An instant snapshot capturing your current state, key decisions made, and outstanding concerns.</li> <li><strong>Open Threads:</strong> Automatically catches dangling ideas you mentioned but haven’t implemented yet.</li> <li><strong>Zero Configuration:</strong> Designed to piggy-back off the existing <code>claude</code> CLI authentication, so there are no extra API keys to set up!</li> </ul> <h2 id="what-it-looks-like">What it looks like</h2> <p>We’ve designed ContextMap’s output to look and act like a high-end, premium report. You get click-to-expand cards, clear icon indicators for successes or failures, and a clean, warm-dark aesthetic.</p> <p>Check out the , which tracks the development of a mockup computational biology genomic foundation model.</p> <h2 id="get-started-today">Get Started Today</h2> <p>ContextMap is available as an open-source tool. To get started, you can literally run:</p> <div class="highlight"><pre tabindex="0" class="chroma"><code class="language-bash" data-lang="bash"><span class="line"><span class="cl">curl -fsSL https://raw.githubusercontent.com/ykai16/ContextMap/master/install.sh <span class="p">|</span> bash </span></span></code></pre></div><p>Then, just type <code>contextmap</code> from any repository where you’ve been working with Claude Code. Let the AI map the AI!</p> <hr> <p><em>Found it useful or have feedback? I’d love to hear your thoughts! Drop an issue or check out the code at the .</em></p> </article> <article> <h1>We are excited to announce ContextMap!</h1> <p>Sat, 21 Feb 2026 00:00:00 +0000</p> <p>We are excited to announce <strong>ContextMap</strong> to provide session intelligence and auto-summarize the project’s evolution across your Claude Code sessions.</p> <p>ContextMap automatically tracks your workflow, maps out critical decisions, and generates beautiful self-contained HTML reports so you never lose your train of thought again.</p> <p> </p> </article> <article> <h1>Catch me at NeurIPS 2025!</h1> <p>Wed, 03 Dec 2025 00:00:00 +0000</p> <p>I’ll be attending <strong>NeurIPS 2025</strong>! Looking forward to connecting with the community and discussing how AI is transforming drug discovery and genomics research!</p> <p> <figure > <div class="flex justify-center "> <div class="w-full" > </div> </div></figure> </p> </article> <article> <h1>Our paper on Golcadomide is published in Blood Cancer Discovery</h1> <p>Wed, 05 Nov 2025 00:00:00 +0000</p> <p>Excited to share that our work on <strong>Golcadomide</strong>, an oral CELMoD agent targeting IKZF1/3 for Diffuse Large B-Cell Lymphoma, has been published in <em>Blood Cancer Discovery</em>!</p> <p>This study demonstrates how molecular glue degraders can selectively eliminate cancer cells by hijacking the ubiquitin-proteasome system.</p> <p> <figure > <div class="flex justify-center "> <div class="w-full" > </div> </div></figure> </p> </article> </main></body></html>