GoPeaks: histone modification peak calling for CUT&amp;Tag

Yashar, William M.; Kong, Garth; VanCampen, Jake; Curtiss, Brittany M; Coleman, Daniel J.; Carbone, Lucia; Yardımcı, Galip Gürkan; Maxson, Julia E.; Braun, Theodore P.

doi:10.1186/s13059-022-02707-w

Cited by 17 publications

(8 citation statements)

References 72 publications

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“…TMM (Trimmed Mean of M-Values) normalization was performed on histone mark samples to accurately account for differences in library composition and sequencing depth. First, peaks were called on control samples against IgG using GoPeaks ( Yashar et al, 2022 ). featureCounts ( Liao et al, 2014 ) was then used to count reads from each replicate inside the peaks for each histone mark across control and fru -/- samples.…”

Section: Methodsmentioning

confidence: 99%

Low-level repressive histone marks fine-tune gene transcription in neural stem cells

Rajan,

Anhezini,

Rives-Quinto

et al. 2023

eLife

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Coordinated regulation of gene activity by transcriptional and translational mechanisms poise stem cells for a timely cell-state transition during differentiation. Although important for all stemness-to-differentiation transitions, mechanistic understanding of the fine-tuning of gene transcription is lacking due to the compensatory effect of translational control. We used intermediate neural progenitor (INP) identity commitment to define the mechanisms that fine-tune stemness gene transcription in fly neural stem cells (neuroblasts). We demonstrate that the transcription factor FruitlessC (FruC) binds cis-regulatory elements of most genes uniquely transcribed in neuroblasts. Loss of fruC function alone has no effect on INP commitment but drives INP dedifferentiation when translational control is reduced. FruC negatively regulates gene expression by promoting low-level enrichment of the repressive histone mark H3K27me3 in gene cis-regulatory regions. Identical to fruC loss-of-function, reducing Polycomb Repressive Complex 2 activity increases stemness gene activity. We propose low-level H3K27me3 enrichment fine-tunes gene transcription in stem cells, a mechanism likely conserved from flies to humans.

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Section: Methodsmentioning

confidence: 99%

Low-level repressive histone marks fine-tune gene transcription in neural stem cells

Rajan,

Anhezini,

Rives-Quinto

et al. 2023

eLife

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“…CUT&Tag and CUT&RUN libraries were aligned to the human genome (hg38) using Bow-tie2 and the following options --local --very-sensitive-local --no-unal --no-mixed --no-dis- cordant --phred33 -I 10 -X 700 (60). Peaks were called using GoPeaks and the following option -mdist 1000 (61). High confidence peaks were defined by presence in 2/2 or 2/3 replicates.…”

Section: Methodsmentioning

confidence: 99%

Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia

Yashar

Curtiss

Coleman

et al. 2022

Preprint

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Clinical responses to kinase inhibitor therapy in acute myeloid leukemia (AML) are limited by the inevitable development of resistance. A major contributor to resistance is early epigenetic adaptation, leading to persistence of a small number of leukemia cells. Here we show that inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) augments the response to inhibitors of the FLT3 kinase in AML. We demonstrate that combined FLT3 and LSD1 inhibition results in synergistic cell death of FLT3-mutant AML cells. The drug combination activates a pro-differentiative epigenetic and transcriptional program while simultaneously suppressing the activity of MYC target genes. High-resolution, multi-modal epigenetic analyses revealed that combined FLT3 and LSD1 inhibition results in the suppression of MYC-bound promoters and the activation of PU.1-bound enhancers. Regulon enrichment analysis in primary AML samples nominated STAT5 as a putative regulator of MYC gene expression. Inhibition of FLT3 results in a loss of STAT5 binding at the MYC blood super-enhancer and a loss of super-enhancer activation. In contrast, LSD1 inhibition prevents the removal of repressive H3K9me1 marks at MYC target genes, resulting in suppression of MYC expression. We validated these findings in 66 primary AML samples including 17 FLT3-ITD-positive AML samples, with the majority demonstrating improved responses with the drug combination. High MYC regulon activity was a predictor of response to the drug combination and RNA-seq on drug-treated AML samples revealed suppression of MYC target genes. Finally, single cell ATAC-seq on primary AML blasts treated ex vivo with the FLT3 and LSD1 inhibitor combination results in a shift from MYC super-enhancer-high to a MYC super-enhancer-low cell state. Collectively, these studies provide preclinical rationale for the investigation of dual FLT3 and LSD1 inhibition in a clinical trial.

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“…PCR duplicates were removed from the sorted bam files using Picard tools (https://broadinstitute.github.io/picard/). The filtered reads were then employed to identify CUT&Tag peaks using MACS2 (81). The overlapped peaks in the two biological replicates were identified by the Irreproducibility Discovery Rate (IDR) (82).…”

Section: Cutandtag and Data Analysismentioning

confidence: 99%

Cyclical transcription factor AP2XII-9 is a key activator for asexual division and apicoplast inheritance inToxoplasma gondiitachyzoite

Shi,

Li,

Xue

et al. 2024

Preprint

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Toxoplasma gondii is an intracellular parasitic protozoan that poses a significant risk to pregnant women and immunocompromised individuals. T. gondii tachyzoites duplicate rapidly in host cells during acute infection through endodyogeny. This highly regulated division process is accompanied by complex gene regulation networks. TgAP2XII-9 is a cyclical transcription factor, but its specific role in the parasite cell cycle is not fully understood. Here, we demonstrate that TgAP2XII-9 is identified as a nuclear transcription factor and is dominantly expressed during the S/M phase of the tachyzoite cell cycle. CUT&Tag results indicate that TgAP2XII-9 targets key genes for the moving junction machinery (RON2, 4, 8) and daughter cell inner membrane complex (IMC). TgAP2XII-9 deficiency resulted in a significant downregulation of rhoptry proteins and rhoptry neck proteins, leading to a severe defect in the invasion and egress efficiency of tachyzoites. Additionally, the loss of TgAP2XII-9 correlated with a substantial downregulation of multiple IMC and apicoplast proteins, leading to disorders of daughter bud formation and apicoplast inheritance, and further contributing to the inability of cell division and intracellular proliferation. Our study reveals that TgAP2XII-9 acts as a critical S/M-phase regulator that orchestrates the endodyogeny and apicoplast division in T. gondii tachyzoite. This study contributes to a broader understanding of the complexity of the parasite's cell cycle and its key regulators.

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GoPeaks: histone modification peak calling for CUT&Tag

Cited by 17 publications

References 72 publications

Low-level repressive histone marks fine-tune gene transcription in neural stem cells

Low-level repressive histone marks fine-tune gene transcription in neural stem cells

Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia

Cyclical transcription factor AP2XII-9 is a key activator for asexual division and apicoplast inheritance inToxoplasma gondiitachyzoite

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