Publications by authors named "Scott Hiebert"

Cancer cells are heterogeneous, each harboring distinct molecular aberrations and are dependent on different genes for their survival and proliferation. While successful targeted therapies have been developed based on driver DNA mutations, many patient tumors lack druggable mutations and have limited treatment options. Here, we hypothesize that new precision oncology targets may be identified through "expression-driven dependency", whereby cancer cells with high expression of a targeted gene are more vulnerable to the knockout of that gene.

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Undifferentiated intestinal stem cells (ISCs) are crucial for maintaining homeostasis and resolving injury. Lgr5+ cells in the crypt base constantly divide, pushing daughter cells upward along the crypt axis where they differentiate into specialized cell types. Coordinated execution of complex transcriptional programs is necessary to allow for the maintenance of undifferentiated stem cells while permitting differentiation of the wide array of intestinal cells necessary for homeostasis.

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Transcriptional dysregulation is a hallmark of diffuse large B cell lymphoma (DLBCL), as transcriptional regulators are frequently mutated. However, our mechanistic understanding of how normal transcriptional programs are co-opted in DLBCL has been hindered by a lack of methodologies that provide the temporal resolution required to separate direct and indirect effects on transcriptional control. We applied a chemical-genetic approach to engineer the inducible degradation of the transcription factor FOXO1, which is recurrently mutated (mFOXO1) in DLBCL.

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Article Synopsis
  • * Deleting certain HDACs in embryonic stem cells (ESCs) unexpectedly reduces the expression of key pluripotency-related transcription factors despite HDACs being generally viewed as repressors.
  • * Inhibiting HDACs and the transcriptional activator BRD4 results in decreased expression of pluripotency genes, indicating that HDACs help maintain pluripotency by regulating enhancer activity and ensuring RNA polymerase II recruitment.
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While reviewers' recommendations can strengthen a manuscript, responding to their concerns can be a tricky and frustrating process for authors. For our special issue on stress, Molecular Cell speaks with Scott Hiebert about his advice for responding to reviewers, crafting an effective revision plan, and involving trainees in the process.

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Undifferentiated intestinal stem cells (ISCs), particularly those marked by , are crucial for maintaining homeostasis and resolving injury. + cells in the crypt base constantly divide, pushing daughter cells upward along the crypt axis, where they differentiate into a variety of specialized cell types. This process requires coordinated execution of complex transcriptional programs, which allow for the maintenance of undifferentiated stem cells while permitting differentiation of the wide array of intestinal cells necessary for homeostasis.

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Transcriptional dysregulation is a key step in oncogenesis, but our understanding of transcriptional control has relied on genetic approaches that are slow and allow for compensation. Chemical-genetic approaches have shortened the time frame for the analysis of transcription factors from days or weeks to minutes. These studies show that while DNA-binding proteins bind to thousands of sites, they are directly required to regulate only a small cadre of genes.

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Recurrent chromosomal rearrangements found in rhabdomyosarcoma (RMS) produce the PAX3-FOXO1 fusion protein, which is an oncogenic driver and a dependency in this disease. One important function of PAX3-FOXO1 is to arrest myogenic differentiation, which is linked to the ability of RMS cells to gain an unlimited proliferation potential. Here, we developed a phenotypic screening strategy for identifying factors that collaborate with PAX3-FOXO1 to block myo-differentiation in RMS.

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Genetic models suggested that SMARCA5 was required for DNA-templated events including transcription, DNA replication, and DNA repair. We engineered a degron tag into the endogenous alleles of SMARCA5, a catalytic component of the imitation switch complexes in three different human cell lines to define the effects of rapid degradation of this key regulator. Degradation of SMARCA5 was associated with a rapid increase in global nucleosome repeat length, which may allow greater chromatin compaction.

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Transcriptional control is a highly dynamic process that changes rapidly in response to various cellular and extracellular cues, making it difficult to define the mechanism of transcription factor function using slow genetic methods. We used a chemical-genetic approach to rapidly degrade a canonical transcriptional activator, PAX3-FOXO1, to define the mechanism by which it regulates gene expression programs. By coupling rapid protein degradation with the analysis of nascent transcription over short time courses and integrating CUT&RUN, ATAC-seq, and eRNA analysis with deep proteomic analysis, we defined PAX3-FOXO1 function at a small network of direct transcriptional targets.

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Cortical interneurons originating in the embryonic medial ganglionic eminence (MGE) diverge into a range of different subtypes found in the adult mouse cerebral cortex. The mechanisms underlying this divergence and the timing when subtype identity is set up remain unclear. We identify the highly conserved transcriptional co-factor MTG8 as being pivotal in the development of a large subset of MGE cortical interneurons that co-expresses Somatostatin (SST) and Neuropeptide Y (NPY).

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Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear.

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Background: All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis.

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Transcriptional changes happen within minutes; however, RNAi or genetic deletion requires days to weeks before transcription networks can be analyzed. This limitation has made it challenging to distinguish direct from indirect targets of sequence-specific transcription factors. This inability to define direct transcriptional targets hinders detailed studies of transcriptional mechanisms.

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Accumulating evidence suggests that many immune responses are influenced by local nutrient concentrations in addition to the programming of intermediary metabolism within immune cells. Humoral immunity and germinal centers (GC) are settings in which these factors are under active investigation. Hypoxia is an example of how a particular nutrient is distributed in lymphoid follicles during an antibody response, and how oxygen sensors may impact the qualities of antibody output after immunization.

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Transcription factors regulate gene networks controlling normal hematopoiesis and are frequently deregulated in acute myeloid leukemia (AML). Critical to our understanding of the mechanism of cellular transformation by oncogenic transcription factors is the ability to define their direct gene targets. However, gene network cascades can change within minutes to hours, making it difficult to distinguish direct from secondary or compensatory transcriptional changes by traditional methodologies.

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Purpose: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients.

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Article Synopsis
  • Researchers are investigating drugs that target chromatin-modifying enzymes like INCB059872, which inhibits Lysine-Specific Demethylase 1 (LSD1) and is currently in phase I clinical trials for myeloid cancers, specifically acute myeloid leukemia (AML).
  • Initial studies suggest LSD1 inhibitors might help differentiate AML cells, but the underlying mechanisms and potential side effects are not fully understood.
  • Using advanced sequencing techniques, scientists found that INCB059872 treatment disrupts CoREST activity and enhances GFI1 gene regulation, leading to the accumulation of certain stem/progenitor cells that may cause low platelet counts (thrombocytopenia) in patients.
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Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that does not respond to endocrine therapy or human epidermal growth factor receptor 2 (HER2)-targeted therapies. Individuals with TNBC experience higher rates of relapse and shorter overall survival compared to patients with receptor-positive breast cancer subtypes. Preclinical discoveries are needed to identify, develop, and advance new drug targets to improve outcomes for patients with TNBC.

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Histone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 (Hdac3) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3 mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal β-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides.

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Histone deacetylase 3 (Hdac3) is a target of the FDA approved HDAC inhibitors, which are used for the treatment of lymphoid malignancies. Here, we used Cd19-Cre to conditionally delete Hdac3 to define its role in germinal center B cells, which represent the cell of origin for many B cell malignancies. Cd19-Cre-Hdac3-/- mice showed impaired germinal center formation along with a defect in plasmablast production.

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In the original version of this article the authors noted that the GEO accession number for the relevant dataset was listed incorrectly as GSE12454.

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Article Synopsis
  • WDR5, a protein associated with chromatin, is a potential target for cancer treatment, focusing on inhibiting a specific area known as the "WIN site."
  • Researchers have created effective WIN site inhibitors that demonstrate how WDR5 interacts with chromatin and affects specific gene expressions.
  • These inhibitors can remove WDR5 from chromatin, leading to decreased gene expression and potential therapeutic implications for various types of cancer.
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  • MTG16 is a corepressor protein that interacts with Kaiso to regulate specific target genes, influencing inflammation and tumor development in cancer.
  • Research using a mouse model of colitis-associated cancer showed that loss of MTG16 worsens tumor growth, while loss of Kaiso in MTG16-deficient mice surprisingly reduced tumor burden back to normal levels.
  • The study's findings suggest that Kaiso plays a crucial role in modifying the effects of MTG16 loss on inflammation and tumorigenesis, indicating that the regulation of these proteins could be important in understanding and potentially treating related cancers.
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The t(8;21) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML). We found that t(8;21) AML were extremely sensitive to THZ1, which triggered apoptosis after only 4 h. We used precision nuclear run-on transcription sequencing (PROseq) to define the global effects of THZ1 and other CDK inhibitors on RNA polymerase II dynamics.

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