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The Kind group uses a combination of single-cell genomics and microscopy methods to study the role of chromatin and epigenetics in gene-regulation control, with a focus on early mouse embryonic development and tumorigenesis.
The aim of the lab is to understand the principles governing cellular decision-making. We are interested in how cells acquire new identities and traits in lineage specification events in mice and in cancer. To this end we employ and continuously develop novel single-cell technologies to delineate these processes with high sensitivity and accuracy.
Key words: Single-cell genomics, epigenetics, spatial genome organization, bioinformatics, gene-regulation, embryogenesis, tumorigenesis
We have developed scDam&T, a method to simultaneously capture protein-DNA interactions and transcriptomes in the same cell (Rooijers et al, 2019, Nature Biotechnology) (Figure 1). This method enables linking transcriptional variability to epigenetic heterogeneity. In addition, scDam&T allows determining cellular identity of cells in complex tissues -such as embryos or tumors- based on transcriptomics, in direct relation to their epigenetic regulatory landscapes (DamID). We are employing scDam&T to obtain a better understanding of the epigenetic mechanisms underlying lineage decisions in early embryogenesis, to identify the epigenetic trajectories of single cells that acquire malignant identities in tumorigenesis and to obtain insight into the role of chromatin in DNA double-strand repair. Furthermore, as we consider technology development a core business of the group, we are continuously exploring ways to obtain richer single-cell datasets.
Mechanisms underlying cell-fate choice in early embryogenesis
A major interest in the group is how gene-expression control is achieved in early embryogenesis. An important contributor to the regulation of gene expression is the spatial positioning of genes within the 3-dimensional space of the nucleus. Chromosomal regions that associate with a thin filamentous lamina layer at the nuclear periphery are generally in an inactive transcriptional state (Guerreiro and Kind, 2019, Curr.Opin.Gen.Dev.). We profiled these genome-lamina interactions in single cells to obtain better understanding in gene-regulation control in pre- and post-implantation embryos (Borsos et al., 2019, Nature) (Figure 2). In addition, we profile the epigenetic landscapes, chromatin accessibility and transcriptome in single cells. We use this approach to understand how gene-expression is controlled and to obtain insight into the regulatory mechanisms that govern cellular decision making in mouse early embryogenesis.
Cell-fate decisions and the role of epigenetics in DNA double-strand repair
Accurate repair of DNA damage is critical for the maintenance of genomic integrity. Despite extensive research into the molecular pathways that sense and repair DNA double-strand breaks (DSBs), comparatively little is known about management of breaks within different genomic and chromatin contexts. This is particularly difficult to study because DSBs occur randomly in the genome, thus every single cell harbors a different DSB-landscape. To study DSB-repair in single cells, we have adapted scDam&T to generate maps of DSB-repair sites in single cells. Further, in the same cells, we also profile genome-wide chromatin states with a chromatin immunocleavage (ChIC) approach to study the relationships between DSB-repair and the local chromatin environment (Figure 3). Because DamID-signals are stable and can be carried-over for multiple generations, we are also looking into ways to exploit this property of DamID to study DSB-repair in the context of cellular decision making.
Tumor-cell trajectories in organoid and mouse models
Tumorigenesis involves the continuous selective adaptation of cells from healthy tissue, to adenoma, carcinoma and eventually metastasis. To obtain detailed insight into this trajectory, it is essential to capture all the stages with single-cell accuracy. We are particularly interested in understanding the role of epigenetics and spatial genome organization in this process. We employ our single-cell genomic methods to study cellular trajectories on route towards malignant metastatic identities. To achieve this, we make use of organoid and mouse models that capture tumorigenesis all the way from the initiating stages towards metastasis.
Rang FJ, de Luca, KL, de Vries SS [...] Kimura H, Bakkers J and Kind J
Markodimitraki CM, Rang FJ [...] Dey SS and Kind J
Rooijers K, Markodimitraki CM [...] Dey SS and Kind J
Borsos M, Perricone SM [...] Torres-Padilla M and Kind J
Guerreiro I and Kind J
Kind J, Pagie L [...] van Oudenaarden A and van Steensel B
Kind J, Pagie L [...] Bickmore WA and van Steensel B
Kind J, Vaquerizas JM [...] Bertone P and Akhtar A
Jop Kind is group leader at the Hubrecht Institute, professor by special appointment of Single Cell Epigenomics at the Radboud University Nijmegen and Oncode Investigator. His group is interested in elucidating the role of chromatin and nuclear architecture in gene-regulation and DNA-repair. The Kind group develops new techniques, such as the recently developed DamID and m6ATracer techniques. These techniques enable them to study genome architecture and protein-DNA interactions in high resolution in single cells. The Kind group uses these techniques to study the role of genome architecture and chromatin context in temporal and spatial control of gene expression in development and disease.
Scientific training and positions
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We are always on the lookout for enthousiastic colleagues. If you are interested, please contact Jop Kind.