These are the main projects currently ongoing in our lab:

Atlas of chromosomal territories
In interphase cells, chromosomes typically occupy discrete portions of the nuclear space known as chromosomal territories or CTs. Despite a large literature on CTs in cultured cells, very little is known about the spatial arrangement and inner structure of CTs in cells in their natural tissue context. In this project, we aim to comprehensively map CTs in different human and mouse tissues and cell types, motivated by the following questions: Are CTs observable in all cell types? Is there a typical shape and radial arrangement of chromosomes in different tissues? Do heterologous chromosomes intermingle, and how is this related to gene expression? To answer these questions, we are using high-throughput DNA fluorescence in situ hybridization (FISH), leveraging on a large DNA FISH probe repository which we have recently established (Gelali et al., Nature Communications 2019) and that is publicly available here: www.ifish4u.org.

Developing methods to assess radial genome organization
While it is clear that the nuclear periphery and center represent distinct environments characterized by a different chromosomal content and by different levels of chromatin compaction and function, we do not know the genome is spatially arranged along individual nuclei radii and how the radial organization of the nucleus is established and maintained. In this project, we are developing both microscopy-based assays (YFISH, RADIANT), as well as high-throughput sequencing methods (GPSeq) that will allow us obtaining genome-wide maps of the radial location of DNA loci, as well as quantifying the radial distribution of chromatin in different tissues and cell types.

Mutational landscapes of lung cancer brain metastases
Lung cancer represents the main cause of cancer mortality around the world and brain metastases are often responsible for the death of patients with lung cancer. While the genomic landscape of primary lung cancers has been widely studied in large-scale consortia such as TCGA and ICGC, very few studies have addressed the genomic landscape of lung cancer brain metastases. In this project, we perform comprehensive genomic analyses and high-throughput imaging of multiple pairs of primary lung cancers and brain metastases, with the goal of identifying potentially target-able mutations and reconstructing the evolutionary history of metastasis.

Genome architecture and fragility in neurodevelopment
Genome instability has been implicated in the pathogenesis of several neurodevelopmental diseases, including autism spectrum disorder and Schizophrenia. In particular, incorrect repair of DNA double-strand breaks (DSBs) has been postulated as a possible cause of mosaic somatic copy number variants, which in turn have been linked to specific neurodevelopmental disorders. In this project, we aim to map endogenous DSBs that arise during the course of differentiation of neuroepithelial stem cells, and link their genome-wide distribution to the genome architecture and gene expression levels. For this purpose, we are applying the BLISS method for genome-wide DSB sequencing which we have recently developed (Yan et al., Nature Communications 2017), together with Hi-C and RNA-Seq, to differentiating human induced pluripotent stem (iPS) cell-derived neurons.