Massively parallel characterization of transcriptional regulatory elements in three diverse human cell types

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 6, 2023

ABSTRACT The human genome contains millions of candidate cis -regulatory elements (CREs) with cell-type-specific activities that shape both health and myriad disease states. However, we lack a functional understanding the sequence features control activity these CREs. Here, used lentivirus-based massively parallel reporter assays (lentiMPRAs) to test regulatory over 680,000 sequences, representing nearly comprehensive set all annotated CREs among three cell types (HepG2, K562, WTC11), finding 41.7% be functional. By testing sequences in orientations, find promoters have significant strand orientation effects. We also observe their 200 nucleotide cores function as non-cell-type-specific ‘on switches’ providing similar expression levels associated gene. In contrast, enhancers weaker effects, but increased tissue-specific characteristics. Utilizing our lentiMPRA data, develop sequence-based models predict CRE high accuracy delineate motifs. Testing an additional library encompassing 60,000 types, further identified factors determine cell-type specificity. Collectively, work provides exhaustive catalog widely lines, showcases how large-scale measurements can dissect grammar.

Язык: Английский

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Massively parallel characterization of regulatory elements in the developing human cortex

Science, Год журнала: 2024, Номер 384(6698)

Опубликована: Май 23, 2024

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays primary human cells from mid-gestation cortex cerebral organoids, we interrogated the cis-regulatory activity 102,767 open chromatin regions, including thousands sequences with cell type-specific accessibility variants associated brain regulation. In cells, identified 46,802 active enhancer 164 that alter activity. Activity was comparable organoids suggesting provide an adequate model for developing cortex. deep learning decoded sequence basis upstream regulators This work establishes a comprehensive catalog functional development.

Язык: Английский

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Massively parallel characterization of transcriptional regulatory elements

Nature, Год журнала: 2025, Номер unknown

Опубликована: Янв. 15, 2025

Abstract The human genome contains millions of candidate cis -regulatory elements (cCREs) with cell-type-specific activities that shape both health and many disease states 1 . However, we lack a functional understanding the sequence features control activity these cCREs. Here used lentivirus-based massively parallel reporter assays (lentiMPRAs) to test regulatory more than 680,000 sequences, representing an extensive set annotated cCREs among three cell types (HepG2, K562 WTC11), found 41.7% sequences were active. By testing in orientations, find promoters have strand-orientation biases their 200-nucleotide cores function as non-cell-type-specific ‘on switches’ provide similar expression levels associated gene. contrast, enhancers weaker orientation biases, but increased tissue-specific characteristics. Utilizing our lentiMPRA data, develop sequence-based models predict cCRE variant effects high accuracy, delineate motifs model combinatorial effects. Testing library encompassing 60,000 all further identified factors determine cell-type specificity. Collectively, work provides catalogue CREs widely lines showcases how large-scale measurements can be dissect grammar.

Язык: Английский

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Chromatin accessibility in the Drosophila embryo is determined by transcription factor pioneering and enhancer activation

Developmental Cell, Год журнала: 2023, Номер 58(19), С. 1898 - 1916.e9

Опубликована: Авг. 8, 2023

Chromatin accessibility is integral to the process by which transcription factors (TFs) read out cis-regulatory DNA sequences, but it difficult differentiate between TFs that drive and those do not. Deep learning models learn complex sequence rules provide an unprecedented opportunity dissect this problem. Using zygotic genome activation in Drosophila as a model, we analyzed high-resolution TF binding chromatin data with interpretable deep performed genetic validation experiments. We identify hierarchical relationship pioneer Zelda involved axis patterning. consistently pioneers proportional motif affinity, whereas patterning augment contexts where they mediate enhancer activation. conclude occurs two tiers: one through pioneering, makes enhancers accessible not necessarily active, second when correct combination of leads

Язык: Английский

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Type I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection

Immunity, Год журнала: 2024, Номер 57(5), С. 1037 - 1055.e6

Опубликована: Апрель 8, 2024

Язык: Английский

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An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression

Cancer Research, Год журнала: 2024, Номер 84(18), С. 3086 - 3100

Опубликована: Июль 11, 2024

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of cancer. mCRPC receptor (AR) inhibitors by amplifying AR signaling or evolving into therapy-resistant subtypes do not depend on AR. Elucidation epigenetic underpinnings these could provide important insights drivers resistance. In this study, we produced chromatin accessibility maps linked to binding lineage-specific transcription factors (TF) performing assay for transposase-accessible sequencing 70 tissue biopsies integrated with transcriptome and whole-genome sequencing. had distinct global profile function. Analysis TF occupancy across accessible revealed 203 TFs associated subtypes. Notably, ZNF263 was identified as putative significant impact gene activity in double-negative subtype (AR- neuroendocrine-), potentially activating MYC targets. Overall, analysis provides valuable changes occur during progression mCRPC. Significance: Integration large cohort transcriptome, whole-genome, ATAC characterizes advanced identifies subtype-specific modulate oncogenic programs.

Язык: Английский

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Transcription factor specificity protein (SP) family in renal physiology and diseases

PeerJ, Год журнала: 2025, Номер 13, С. e18820 - e18820

Опубликована: Янв. 20, 2025

Dysregulated specificity proteins (SPs), members of the C2H2 zinc-finger family, are crucial transcription factors (TFs) with implications for renal physiology and diseases. This comprehensive review focuses on role SP family members, particularly SP1 SP3, in pathology. A detailed analysis their expression cellular localization healthy human kidney is presented, highlighting involvement fatty acid metabolism, electrolyte regulation, synthesis important molecules. The also delves into diverse roles SPs various diseases, including ischemia/reperfusion injury, diabetic nephropathy, interstitial fibrosis, lupus nephritis, elucidating molecular mechanisms potential as therapeutic targets. further discusses pharmacological modulation its treatment. Our findings provide a understanding health disease, offering new avenues targeted interventions precision medicine nephrology.

Язык: Английский

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Molecular signature of primate astrocytes reveals pathways and regulatory changes contributing to human brain evolution

Cell stem cell, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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TF Profiler: a transcription factor inference method that broadly measures transcription factor activity and identifies mechanistically distinct networks

Genome biology, Год журнала: 2025, Номер 26(1)

Опубликована: Апрель 9, 2025

TF Profiler is a method of inferring transcription factor (TF) regulatory activity, i.e., when present and actively participating in the regulation transcription, directly from nascent sequencing assays such as PRO-seq GRO-seq. While ChIP have measured DNA localization, they fall short identifying where effector domain active. Our uses RNA polymerase activity to infer across hundreds data sets factors. broadly applicable, providing insights on any sample for with known binding motif.

Язык: Английский

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Massively parallel characterization of psychiatric disorder-associated and cell-type-specific regulatory elements in the developing human cortex

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Фев. 15, 2023

Abstract Nucleotide changes in gene regulatory elements are important determinants of neuronal development and disease. Using massively parallel reporter assays primary human cells from mid-gestation cortex cerebral organoids, we interrogated the cis -regulatory activity 102,767 sequences, including differentially accessible cell-type specific regions developing single-nucleotide variants associated with psychiatric disorders. In cells, identified 46,802 active enhancer sequences 164 disorder-associated that significantly alter activity. Activity was comparable organoids suggesting provide an adequate model for cortex. deep learning, decoded sequence basis upstream regulators This work establishes a comprehensive catalog functional development. One Sentence Summary We identify enhancers disorder effects organoids.

Язык: Английский

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