Organizational principles of the primate cerebral cortex at the single-cell level DOI
Renrui Chen, Pengxing Nie, Liangxiao Ma

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 7, 2024

Abstract The primate cerebral cortex, the major organ for cognition, consists of an immense number neurons. However, organizational principles governing these neurons remain unclear. By accessing single-cell spatial transcriptome over 25 million neuron cells across entire macaque we discovered that distribution within cortical layers is highly non-random. Strikingly, three-quarters are located in distinct neuronal clusters. Within clusters, different cell types tend to collaborate rather than function independently. Typically, excitatory clusters mainly consist excitatory-excitatory combinations, while inhibitory primarily contain excitatory-inhibitory combinations. Both cluster have roughly equal numbers each layer. Importantly, most and form partnerships, indicating a balanced local network correlating with specific functional regions. These findings suggest brain regions cortex may exhibit similar mechanisms at population level.

Language: Английский

Genetic regulation of cell type–specific chromatin accessibility shapes brain disease etiology DOI
Biao Zeng, Jaroslav Bendl, Chengyu Deng

et al.

Science, Journal Year: 2024, Volume and Issue: 384(6698)

Published: May 23, 2024

Nucleotide variants in cell type-specific gene regulatory elements the human brain are risk factors for disease. We measured chromatin accessibility 1932 aliquots of sorted neurons and non-neurons from 616 postmortem brains identified 34,539 open regions with quantitative trait loci (caQTLs). Only 10.4% caQTLs shared between non-neurons, which supports genetic regulation regulome. Incorporating allele-specific improves statistical fine-mapping refines molecular mechanisms that underlie disease risk. Using massively parallel reporter assays induced excitatory neurons, we screened 19,893 QTLs functional impact 476 variants. Combined, this comprehensive resource captures variation regulome provides insights into etiology.

Language: Английский

Citations

14
Rapid and quantitative functional interrogation of human enhancer variant activity in live mice DOI Creative Commons
Ethan W. Hollingsworth, Taryn Audrey Liu, Joshua A. Alcantara

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 6, 2025

Abstract Functional analysis of non-coding variants associated with congenital disorders remains challenging due to the lack efficient in vivo models. Here we introduce dual-enSERT, a robust Cas9-based two-color fluorescent reporter system which enables rapid, quantitative comparison enhancer allele activities live mice less than two weeks. We use this technology examine and measure gain- loss-of-function effects previously linked limb polydactyly, autism spectrum disorder, craniofacial malformation. By combining dual-enSERT single-cell transcriptomics, characterise gene expression cells where is normally ectopically active, revealing candidate pathways that may lead misregulation. Finally, demonstrate widespread utility by testing fifteen uncharacterised rare common neurodevelopmental disorders. In doing so identify reproducibly alter activity OTX2 MIR9-2 brain enhancers, implicating them autism. Dual-enSERT thus allows researchers go from identifying comparative embryos under

Language: Английский

Citations

1
Massively parallel characterization of transcriptional regulatory elements DOI Creative Commons
Vikram Agarwal, Fumitaka Inoue, Max Schubach

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 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.

Language: Английский

Citations

1
Modelling human brain development and disease with organoids DOI
Marcella Birtele, Madeline A. Lancaster, Giorgia Quadrato

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 12, 2024

Language: Английский

Citations

6
SuPreMo: a computational tool for streamlining in silico perturbation using sequence-based predictive models DOI Creative Commons
Ketrin Gjoni, Katherine S. Pollard

Bioinformatics, Journal Year: 2024, Volume and Issue: 40(6)

Published: May 25, 2024

The increasing development of sequence-based machine learning models has raised the demand for manipulating sequences this application. However, existing approaches to edit and evaluate genome using have limitations, such as incompatibility with structural variants, challenges in identifying responsible sequence perturbations, need vcf file inputs phased data. To address these bottlenecks, we present Sequence Mutator Predictive Models (SuPreMo), a scalable comprehensive tool performing supporting silico mutagenesis experiments. We then demonstrate how pairs reference perturbed can be used prioritize pathogenic variants or discover new functional sequences.

Language: Английский

Citations

5
Organizational Principles of the Primate Cerebral Cortex at the Single‐Cell Level DOI Creative Commons
Renrui Chen, Pengxing Nie, Liangxiao Ma

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

Abstract The primate cerebral cortex, the major organ for cognition, consists of an immense number neurons. However, organizational principles governing these neurons remain unclear. By accessing single‐cell spatial transcriptome over 25 million neuron cells across entire macaque it is discovered that distribution within cortical layers highly non‐random. Strikingly, three‐quarters are located in distinct neuronal clusters. Within clusters, different cell types tend to collaborate rather than function independently. Typically, excitatory clusters mainly consist excitatory‐excitatory combinations, while inhibitory primarily contain excitatory‐inhibitory combinations. Both cluster have roughly equal numbers each layer. Importantly, most and form partnerships, indicating a balanced local network correlating with specific functional regions. These conserved mouse findings suggest brain regions cortex may exhibit similar mechanisms at population level.

Language: Английский

Citations

0
Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies DOI Creative Commons
Jinshou Yang,

Feihan Zhou,

Xiyuan Luo

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 3, 2025

Abstract Transcriptional dysregulation is a hallmark of cancer initiation and progression, driven by genetic epigenetic alterations. Enhancer reprogramming has emerged as pivotal driver carcinogenesis, with cells often relying on aberrant transcriptional programs. The advent high-throughput sequencing technologies provided critical insights into enhancer events their role in malignancy. While targeting enhancers presents promising therapeutic strategy, significant challenges remain. These include the off-target effects enhancer-targeting technologies, complexity redundancy networks, dynamic nature reprogramming, which may contribute to resistance. This review comprehensively encapsulates structural attributes enhancers, delineates mechanisms underlying malignant transformation, evaluates opportunities limitations associated cancer.

Language: Английский

Citations

0
2024 ASHG Scientific Achievement Award DOI Creative Commons
Nadav Ahituv

The American Journal of Human Genetics, Journal Year: 2025, Volume and Issue: 112(3), P. 473 - 477

Published: March 1, 2025

Language: Английский

Citations

0
Deep-learning prediction of gene expression from personal genomes DOI Creative Commons
Shiron Drusinsky, Sean Whalen, Katherine S. Pollard

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 27, 2024

Models that predict RNA levels from DNA sequences show tremendous promise for decoding tissue-specific gene regulatory mechanisms, revealing the genetic architecture of traits, and interpreting noncoding variation. Existing methods take two different approaches: 1) associating expression with linear combinations common variants (training across individuals on single genes), or 2) learning genome-wide sequence-to-expression rules neural networks loci using a reference genome). Since limitations both strategies have been highlighted recently, we sought to combine sequence context provided by deep information cross-individual training. We utilized fine-tuning develop Performer, model accuracy approaching cis-heritability most genes. Performer prioritizes allele frequency spectrum disrupt motifs, fall in annotated elements, functional evidence modulating expression. While obstacles remain personalized prediction, our findings establish as viable strategy.

Language: Английский

Citations

3
Advancing evolutionary medicine with complete primate genomes and advanced biotechnologies DOI
Kaiyue Ma, Xiangyu Yang, Yafei Mao

et al.

Trends in Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

Citations

3