Doctoral (PhD) student position to study ‘Epigenetic mechanisms underlying human liver diseases’

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.

The position will be placed in the laboratory of Prof. Eckardt Treuter which conducts pre-clinical research at the crossroads between epigenomics, metabolism, inflammation and disease. The research aims at better understanding how the epigenome controls metabolic and inflammatory pathways in the context of obesity, type 2 diabetes, fatty liver disease and atherosclerosis. Epigenetic alterations that trigger changes in epigenome activity and gene expression are fundamental reprogramming events that are associated with the development of these diseases. However, the underlying regulatory mechanisms, the critical components, and the causal relationship of these associations are currently poorly defined. The laboratory addresses these issues utilizing a multidisciplinary approach,including molecularbiology, biochemistry, genomics and epigenomics approaches, in collaboration with clinicians to study human tissue samples.

https://ki.se/en/bionut/epigenetic-mechanisms-underlying-metabolic-inflammatory-diseases-eckardt- treuter

The laboratory is placed in the Department of Biosciences and Nutrition at Karolinska’s South Campus, a creative and open environment.

The project:
AIM: The purpose of this PhD project is to identify epigenetic signatures in human hepatocytes, with an emphasis on functionally distinct enhancers and silencers, along with exploring epigenetic mechanisms and alterations that underly liver diseases in humans.

RATIONALE: Metabolic and inflammatory signals induce functionally coupled epigenetic and transcriptional alterations in all cell types of the liver that underly severe liver diseases, including non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH) and hepatocellular carcinoma (HCC). These alterations are tightly controlled at level of gene expression by so-called cis-regulatory elements including enhancers and silencers, that are also subject to individual genetic variation of disease susceptibility via single nucleotide polymorphisms (SNPs). The regulatory chromatin landscape and disease-associated patient-specific alterations thereof are currently poorly characterized for the human liver, with hepatocytes being the most abundant and crucial cell type.

SIGNIFICANCE: Epigenetic alterations of chromatin states are suspected to contribute to metabolic and inflammatory disease pathways but have not yet been systematically mapped in the human liver. Patient-specific epigenetic signatures may become useful for the diagnosis and therapy of liver diseases (‘record the past and predict the future’).

Duties:
The PhD student will establish and manipulate human hepatocyte cultures in 2D and 3D. These models will be used (1) to identify candidate enhancers and silencers and alterations in response to different disease-relevant signaling conditions, (2) to uncover molecular features that distinguish enhancers and silencers and underly signaling-induced alterations, and (3) to determine individual epigenetic signatures from healthy vs. diseased livers to identify disease-associated alterations. Integrated analysis of disease-linked SNPs will explore how genetic and epigenetic alterations influence each other in hepatocytes. Candidate causal alterations will be functionally characterized using in our laboratory established techniques (PMID: 30975991; PMID: 30825152; PMID: 33503407).

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 seeking a highly motivated and talented individual with a degree in nutritional science, biomedicine, biochemistry, genetics or related fields. A solid wet lab experience in the isolation and cultivation of primary human hepatocytes from healthy and diseased liver tissues (cancer, steatosis, cirrhosis), along with a strong theoretical background in human liver physiology and disease, is required for this position. This includes 2D and 3D hepatocyte cultures, functional assessments and viability testing, sample preparation and standard methods for RNA, DNA, chromatin and protein analysis. Since the focus of this PhD project is on human liver pathways and clinical relevance, experience with rodent liver models is not required. Desired is further someone who is already familiar with working in a clinical environment, BSL-2 laboratory, GMP, in organizing, handling and biobanking patient samples, and in writing ethical permit and biobank applications. Previous experience in data processing, compilation and statistical analysis is an additional merit for this position.

The successful candidate is driven by a great curiosity for biomedical research aimed at exploring epigenetic mechanisms contributing to liver dysfunction in human diseases, willing to tackle challenging tasks with a problem-solving and positive mindset, has excellent written and oral communication skills, and can work focused both independently and as a cooperative team player.

We put great importance to personal qualities.

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.