Doctoral (PhD) position in Molecular Biology & Bioinformatics (single-cell genomics) at Karolinska Institutet

To be a doctoral student means to devote oneself to a research project under supervision of experienced researchers and following an individual study plan. For a doctoral degree, the equivalent of four years of full-time doctoral education is required.

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 past 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.). 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. More recently, we have been studying X-chromosome upregulation using single-cell transcriptomics. The single active X-chromosome in both male and female cells become 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 frequenciesfor X-linked genes (Nature Structural & Molecular Biology 2019). This represents a Breakthrough to the Mechanism of Dosage Compensation. 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 (bioRxiv). This study provides unprecedented insights into the dynamics of mammalian X-chromosome upregulation, identifying "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.

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.

Correct balance of gene expression dosage is vital for normal cell function and homeostasis. Chromosomal copy number variation (CNV) results in imbalance of hundreds of genes in a sweep and is generally not well tolerated at the cell-system level. The X chromosome stands as a remarkably exception in this context since female cells naturally carry two copies while male cells carry only one. Your research will dissect fundamental mechanism of X-chromosome dosage compensation, i.e. how our cells can modulate transcription X-chromosome-wide to resolve gene-dose imbalance. Together, we aim to undercover how the X chromosome (present as only one active copy per cell in each sex) achieves transcriptional hyperactivation to balance its expression levels relative to the autosomal (diploid) part of the genome and gene-expression network. The Reinius lab is currently in the unique position to experimentally discern this outstanding question, thanks to our recent breakthroughs (Larsson 2019 Nature Structural & Molecular Biology, Lentini 2021 Nature Communications). You will also map and dissect mechanisms of autosomal dosage compensation occurring in parts of the genome, with the goal to reveal general principles by which some CNVs are tolerated by the cell system and others lead to loss of homeostasis, and potentially, cancer.

You will employ state-of-the-art RNA/DNA-sequencing technology and advanced bioinformatical approaches to mechanistically expose how the cell can selectively elevate expression of an entire chromosome copy. Such information would have far-reaching implications and applications in biomedicine and may open new avenues in precision medicine, and potentially future therapy of aneuploidy by modulation of dosage compensation.

As a doctoral student, you will use high-throughput RNA/DNA sequencing methods and data to uncover the molecular mechanism of dosage compensation. In case of a wet-lab oriented PhD: You will take active roles in experimental design and use cutting-edge RNA/DNA-seq methods to generate primary data from mouse and human. You are also expected to take an active role in the bioinformatical analyses of the generated data. In case of a bioinformatics-oriented PhD: You will take active roles in experimental design and will perform in-depth analyses of RNA/DNA-seq data generated from mouse and human. You are also expected to perform minor teaching duties at the department as well as minor administrative/communal duties in the lab. The research involves experiments performed on tissues derived from mouse, and therefore you must be willing to work with mice (wet-lab oriented position) or data generated from mouse (bioinformatician). All animal work is performed under strict compliance of Swedish laws and ethical regulations. You will also attend PhD-level courses to fulfil the requirements for Doctoral Degree at Karolinska Institutet.

A creative and inspiring environment full of expertise and curiosity. Karolinska Institutet is one of the world's leading medical universities. Our vision is to pursue the development of knowledge about life and to promote a better health for all. At Karolinska Institutet, we conduct successful medical research and hold the largest range of medical education in Sweden. As a doctoral student you are offered an individual research project, a well-educated supervisor, a vast range of elective courses and the opportunity to work in a leading research group. Karolinska Institutet collaborates with prominent universities from all around the world, which ensures opportunities for international exchanges. You will be employed on a doctoral studentship which means that you receive a contractual salary. Employees also have access to our modern gym for free and receive reimbursements for medical care.

In order to participate in the selection for a doctoral position, you must meet the following general (A) and specific (B) eligibility requirements at latest by the application deadline.

It is your responsibility to certify eligibility by following the instructions on the web page Entry requirements (eligibility) for doctoral education.

A) General eligibility requirement

You meet the general eligibility requirement for doctoral/third-cycle/PhD education if you:

Follow the instructions on the web page Entry requirements (eligibility) for doctoral education.

*If you claim equivalent knowledge, follow the instructions on the web page Assessing equivalent knowledge for general eligibility for doctoral education.

B) Specific eligibility requirement

You meet the specific eligibility requirement for doctoral/third-cycle/PhD education if you:

- Show proficiency in English equivalent to the course English B/English 6 at Swedish upper secondary school.

Follow the instructions on the web page English language requirements for doctoral education.

Verification of your documents Karolinska Institutet checks the authenticity of your documents. Karolinska Institutet reserves the right to revoke admission if supporting documents are discovered to be fraudulent. Submission of false documents is a violation of Swedish law and is considered grounds for legal action.

(A) and (B)can only be certified by the documentation requirement for doctoral education .

We are looking for an enthusiastic and highly motivated candidate who has a degree in Genomics, Bioinformatics, Molecular Biology, Biomedicine, or Biochemistry. Proven experiences in RNA biology, gene regulation, transcriptome-wide studies, mammalian cell or tissue culture techniques, animal science, bioinformatics and programming for statistical computing are particularly advantageous. A strong interest in interdisciplinary experimental method development and creative thinking abilities are essential. Applicants wishing to integrate computational and experimental biology approaches are especially encouraged to apply.

The ideal candidate should be collaborative, scientifically adventurous, curiosity-driven, and should bring independent and original ideas into the project. Any previous records of independent research as well as productive interactions within a multi-disciplinary team environment (e.g. first- or co-author publications) are advantageous. Since the applicant will work in a multidisciplinary environment the ability to work with other scientist and good communication skills (proficiency in spoken and written English) are necessary. Since some of our experiments are performed on cells and tissues derived from mouse, the applicant must be willing to perform animal research.

The doctoral student will be employed on a doctoral studentship maximum 4 years full-time.

Submit your application and supporting documents through the Varbi recruitment system. Use the button in the top right corner and follow the instructions. We prefer that your application is written in English, but you can also apply in Swedish.

Your application must contain the following documents:

- A personal letter and a curriculum vitae
- Degree projects and previous publications, if any
- Any other documentation showing the desirable skills and personal qualities described above
- Documents certifying your general eligibility (see A above)
- Documents certifying your specific eligibility (see B above)

A selection will be made among eligible applicants on the basis of the ability to benefit from doctoral education. The qualifications of the applicants will be evaluated on an overall basis.

Karolinska Institutet uses the following bases of assessment:

- Documented subject knowledge of relevance to the area of research
- Analytical skill
- Other documented knowledge or experience that may be relevant to doctoral studies in the subject.

All applicants will be informed when the recruitment is completed.

Lab homepage: www.reiniuslab.com/News

KI official homepage:https://ki.se/en