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Characterization of structural variants in KOLF2.1J iPSCs and their potential impact on neocortical organoid differentiation

ABSTRACT: Identification of structural variants in KOLF2.1J

PROVIDER: PRJEB90627 | ENA |

REPOSITORIES: ENA

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Dataset's files

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			Action	DRS
	(T2T)EXP_REFINEFINAL1.cmap.gz	Other
	(T2T)EXP_REFINEFINAL1_full.xmap.gz	Other
	(hg38)EXP_REFINEFINAL1.cmap.gz	Other
	(hg38)EXP_REFINEFINAL1_full.xmap.gz	Other
	KOLF_T2T_GA_Annotated_SV.smap.gz	Other

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KOLF2.1J iPSCs carry CNVs associated with neurodevelopmental disorders.

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Large structural variants in KOLF2.1J are unlikely to compromise neurological disease modelling.

Project description:Gracia-Diaz and colleagues analysed high-density DNA microarray and whole genome sequencing (WGS) data from the KOLF2.1J 'reference' human induced pluripotent stem cell (hiPSC) line1, and report the presence of five high-confidence heterozygous copy number variants (CNVs) at least 100kbp in length2. Since three of these CNVs span coding genes, some of which have been associated with neurodevelopmental disease, the authors raise the concern that these CNVs may compromise the utility of KOLF2.1J for neurological disease modelling. We appreciate their thorough analysis and thoughtful interpretation, and agree that potential users of this line should be made aware of all cases where KOLF2.1J differs from the reference genome. However, we believe that the benefits from the widespread use of KOLF2.1J outweigh the potential risks that might arise from the identified CNVs.

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Structural characterization of ribosome variants

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KOLF2.1J iTF-Microglia: A standardized platform to study microglial transcriptional regulatory networks in CNS disease [Hi-C]

Project description:Understanding transcriptional regulatory networks (TRNs) in microglia is key to uncovering mechanisms driving central nervous system (CNS) disorders. Human iPSC-derived models offer a tractable system for studying microglia, yet variability between lines has limited reproducibility. Here, we use the standardized KOLF2.1J iTF line to rapidly generate microglia-like cells (iTF-Microglia) and profile TRNs under homeostatic and inflammatory conditions. iTF-Microglia closely resemble primary brain microglia at both transcriptomic and epigenomic levels. Integrative analyses reveal microglia-enriched candidate cis-regulatory elements (cCREs) and dynamic enhancer remodeling upon differentiation and LPS+IFNG stimulation, involving key transcription factors (TFs) including NF-kB, IRF, and STAT families. TRNs active in iTF-Microglia are enriched for genetic variants linked to Alzheimer’s disease and other CNS disorders. These findings establish KOLF2.1J iTF-Microglia as a reproducible and genetically tractable platform for studying human microglial gene regulation and provide mechanistic insight into how TRN remodeling may contribute to CNS disease risk.

2025-09-10 | GSE299830 | GEO

KOLF2.1J iTF-Microglia: A standardized platform to study microglial transcriptional regulatory networks in CNS disease [RNA-seq]

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KOLF2.1J iTF-Microglia: A standardized platform to study microglial transcriptional regulatory networks in CNS disease [ChIP-seq]

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KOLF2.1J iTF-Microglia: A standardized platform to study microglial transcriptional regulatory networks in CNS disease [ATAC-seq]

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High density SNP array and reanalysis of genome sequencing uncovers CNVs associated with neurodevelopmental disorders in KOLF2.1J iPSCs.

Project description:The KOLF2.1J iPSC line was recently proposed as a reference iPSC to promote the standardization of research studies in the stem cell field. Due to overall good performance differentiating to neural cell lineages, high gene editing efficiency, and absence of genetic variants associated to neurological disorders KOLF2.1J iPSC line was particularly recommended for neurodegenerative disease modeling. However, our work uncovers that KOLF2.1J hPSCs carry heterozygous small copy number variants (CNVs) that cause DTNBP1, JARID2 and ASTN2 haploinsufficiencies, all of which are associated with neurological disorders. We further determine that these CNVs arose in vitro over the course of KOLF2.1J iPSC generation from a healthy donor-derived KOLF2 iPSC line and affect the expression of DNTBP1, JARID2 and ASTN2 proteins in KOLF2.1J iPSCs and neural progenitors. Therefore, our study suggests that KOLF2.1J iPSCs carry genetic variants that may be deleterious for neural cell lineages. This data is essential for a careful interpretation of neural cell studies derived from KOLF2.1J iPSCs and highlights the need for a catalogue of iPSC lines that includes a comprehensive genome characterization analysis.

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Structural variants drive context dependent oncogene activation in cancer

Project description:Higher order chromatin structure is important for regulation of genes by distal regulatory sequences. Structural variants that alter 3D genome organization can lead to enhancer-promoter rewiring and human disease, particularly in the context of cancer. However, only a small minority of structural variants are associated with altered gene expression and it remains unclear why certain structural variants lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific rearrangements on oncogene activation. By analyzing Hi-C data from 92 cancer cell lines and patient samples, we identified loci affected by recurrent alterations to 3D genome structure, including oncogenes such as MYC, TERT, and CCND1. Using CRISPR/Cas9 genome engineering to generate de novo structural variants, we show that oncogene activity can be predicted using “Activity-by-Contact” models that consider partner region chromatin contacts and enhancer activity. However, Activity-by-Contact models are only predictive of specific subsets of genes in the genome, suggesting that different classes of genes engage in distinct modes of regulation by distal regulatory elements. These results indicate that structural variants that alter 3D genome organization are widespread in cancer genomes and begin to illustrate predictive rules for the consequences of structural variants on oncogene activation.

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Integrative Analysis of Pathogenic Structural Variants in Leukemia Genomes

Project description:Pathogenic Structural Variants in Leukemia Genomes

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