the Reinius lab
OUR RESEARCH aims to reveal fundamental features of gene regulation, and in particular the regulation of active versus inactive chromatin. Main topics of the lab are X-chromosome inactivation and dosage compensation. The X chromosome is a unique genetic environment. Female cells contain two X chromosomes while male cells contain one. To balance the X-gene dose in female cells one X copy is kept transcriptionally silenced by the process of X-chromosome inactivation. This is achieved by remarkable remodeling of the inactive X chromosome, which drastically alters its chromatin structure, methylation patterns, and three-dimensional conformation, ultimately suppressing the expression of most of its genes. By characterizing the epigenetic framework of X-chromosome inactivation, we may reveal key features of gene regulation and cellular systems. During the last years, Reinius and colleagues pioneered the use of single-cell RNA-seq in the study of X-inactivation (Science 2014, Nature Reviews Genetics 2015, Cell 2016, Nature Genetics 2016 etc., see Publications ). Currently the Reinius lab is working to determine the X-inactive landscape across a wide range of in vivo tissues and cell types. This is accomplished by a synthesis of newly developed concepts and techniques, including single-cell RNA-sequencing, chromatin accessibility and modification assays, mouse genetics and transgenics, and recently advanced computational methods for the analysis of allele-specific gene expression. The expected outcome of the research is of broad biomedical significance, and may reveal the regulatory underpinnings of variable expressivity and incomplete penetrance of X-linked genetic disorders.
- A MECHANISTIC BREAKTHROUGH: Recently, we have been studying X-chromosome upregulation using single-cell transcriptomics. The single active X-chromosome in both male and female cells cells becomes hyper activated to balance the gene dose with the diploid autosomal part of the genome. We discovered that this hyper activation is achieved by increased transcriptional burst frequencies for X-linked genes (article in Nature Structural & Molecular Biology 2019). This represents a Breakthrough to the Mechanism of Dosage Compensation. An excellent News & Views feature on this study is available here: Rapid transcriptional bursts upregulate the X chromosome, authored by Xinxian Deng & Christine M. Disteche. Furthermore, we have now characterized the allele-specific X-upregulation dynamics throughout the early in vivo development of a mammal (mouse) for the first time and performed the first direct analysis of epigenetic changes upon X-upregulation establishment. This study identifies provides unprecedented insights into the dynamics of mammalian X-chromosome upregulation, indentifying "Elastic X upregulation". Our results prompt a revised model of the chain in events of allelic regulation by X-upregulation and X-inactivation in unitedly achieving stable cellular levels of X-chromosome transcripts (read the preprint on bioRxiv; paper under review).
Advancing RNA/DNA sequencing technology: High-throughput sequencing is key to our work, and is increasingly utilized in biomedicine. We are working to develop and improve methods for RNA and DNA sequencing, tailoring the methods to maximize information yield in the context of specific assays.
LOCATION: The Reinius lab is placed at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, an international and vibrant research environment. Our Division, Biomaterials, is located at Biomedicum, KI Solna Campus, a purpose-built facility for experimental medical research. It hosts research groups with diverse backgrounds, from cell biology to biophysics, forming a unique interdisciplinary cluster of expertise in Molecular Biology and Biomedicine.
Karolinska Institutet, Solna, Stockholm