Bio

Professional Education


  • PhD, Faculty of Medicine, Uppsala University, Molecular Genetics (2017)
  • MSc, Vienna University of Life Sciences, Quantitative Genetics (2011)
  • MSc, SLU, Sweden, Molecular Genetics (2011)
  • BSc, Ain Shams University, Animal Sciences (2007)

Stanford Advisors


Patents


  • Shady Younis, Wael Kamel, Göran Akuslarvi, Leif Andersson. "Sweden Patent WO2018143874A1 Methods for identifying new therapeutic agents", Jan 30, 2018

Publications

All Publications


  • ZBED6 negatively regulates insulin production, neuronal differentiation, and cell aggregation in MIN6 cells FASEB JOURNAL Wang, X., Jiang, L., Wallerman, O., Younis, S., Yu, Q., Klaesson, A., Tengholm, A., Welsh, N., Andersson, L. 2019; 33 (1): 88–100

    Abstract

    Zinc finger BED domain containing protein 6 ( Zbed6) has evolved from a domesticated DNA transposon and encodes a transcription factor unique to placental mammals. The aim of the present study was to investigate further the role of ZBED6 in insulin-producing cells, using mouse MIN6 cells, and to evaluate the effects of Zbed6 knockdown on basal β-cell functions, such as morphology, transcriptional regulation, insulin content, and release. Zbed6-silenced cells and controls were characterized with a range of methods, including RNA sequencing, chromatin immunoprecipitation sequencing, insulin content and release, subplasma membrane Ca2+ measurements, cAMP determination, and morphologic studies. More than 700 genes showed differential expression in response to Zbed6 knockdown, which was paralleled by increased capacity to generate cAMP, as well as by augmented subplasmalemmal calcium concentration and insulin secretion in response to glucose stimulation. We identified >4000 putative ZBED6-binding sites in the MIN6 genome, with an enrichment of ZBED6 sites at upregulated genes, such as the β-cell transcription factors v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and Nk6 homeobox 1. We also observed altered morphology/growth patterns, as indicated by increased cell clustering, and in the appearance of axon-like Neurofilament, medium polypeptide and tubulin β 3, class III-positive protrusions. We conclude that ZBED6 acts as a transcriptional regulator in MIN6 cells and that its activity suppresses insulin production, cell aggregation, and neuronal-like differentiation.-Wang, X., Jiang, L., Wallerman, O., Younis, S., Yu, Q., Klaesson, A., Tengholm, A., Welsh, N., Andersson, L. ZBED6 negatively regulates insulin production, neuronal differentiation, and cell aggregation in MIN6 cells.

    View details for DOI 10.1096/fj.201600835R

    View details for Web of Science ID 000457401500007

    View details for PubMedID 29957057

  • Dissection of the cellular function of the ZBED6 transcription factor in mouse myoblast cells using gene editing, RNAseq and proteomics biorxiv Younis, S., Naboulsi, R., Wang, X., Welsh, N., Andersson, L. 2019

    View details for DOI 10.1101/540914

  • Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Younis, S., Kamel, W., Falkeborn, T., Wang, H., Yu, D., Daniels, R., Essand, M., Hinkula, J., Akusjarvi, G., Andersson, L. 2018; 115 (16): E3808–E3816

    Abstract

    The zinc finger CCCH-type containing 11A (ZC3H11A) gene encodes a well-conserved zinc finger protein that may function in mRNA export as it has been shown to associate with the transcription export (TREX) complex in proteomic screens. Here, we report that ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During an adenovirus infection, the ZC3H11A protein and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription take place. Knockout (KO) of ZC3H11A in HeLa cells demonstrated that several nuclear-replicating viruses are dependent on ZC3H11A for efficient growth (HIV, influenza virus, herpes simplex virus, and adenovirus), whereas cytoplasmic replicating viruses are not (vaccinia virus and Semliki Forest virus). High-throughput sequencing of ZC3H11A-cross-linked RNA showed that ZC3H11A binds to short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. We show that the RNA-binding property of ZC3H11A is crucial for its function and localization. In ZC3H11A KO cells, the adenovirus fiber mRNA accumulates in the cell nucleus. Our results suggest that ZC3H11A is important for maintaining nuclear export of mRNAs during stress and that several nuclear-replicating viruses take advantage of this mechanism to facilitate their replication.

    View details for DOI 10.1073/pnas.1722333115

    View details for Web of Science ID 000430191900026

    View details for PubMedID 29610341

    View details for PubMedCentralID PMC5910864

  • The ZBED6-IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Younis, S., Schonke, M., Massart, J., Hjortebjerg, R., Sundstrom, E., Gustafson, U., Bjornholm, M., Krook, A., Frystyk, J., Zierath, J. R., Andersson, L. 2018; 115 (9): E2048–E2057

    Abstract

    A single nucleotide substitution in the third intron of insulin-like growth factor 2 (IGF2) is associated with increased muscle mass and reduced subcutaneous fat in domestic pigs. This mutation disrupts the binding of the ZBED6 transcription factor and leads to a threefold up-regulation of IGF2 expression in pig skeletal muscle. Here, we investigated the biological significance of ZBED6-IGF2 interaction in the growth of placental mammals using two mouse models, ZBED6 knock-out (Zbed6-/-) and Igf2 knock-in mice that carry the pig IGF2 mutation. These transgenic mice exhibit markedly higher serum IGF2 concentrations, higher growth rate, increased lean mass, and larger heart, kidney, and liver; no significant changes were observed for white adipose tissues. The changes in body and lean mass were most pronounced in female mice. The phenotypic changes were concomitant with a remarkable up-regulation of Igf2 expression in adult tissues. Transcriptome analysis of skeletal muscle identified differential expression of genes belonging to the extracellular region category. Expression analysis using fetal muscles indicated a minor role of ZBED6 in regulating Igf2 expression prenatally. Furthermore, transcriptome analysis of the adult skeletal muscle revealed that this elevated expression of Igf2 was derived from the P1 and P2 promoters. The results revealed very similar phenotypic effects in the Zbed6 knock-out mouse and in the Igf2 knock-in mouse, showing that the effect of ZBED6 on growth of muscle and internal organs is mediated through the binding site in the Igf2 gene. The results explain why this ZBED6 binding site is extremely well conserved among placental mammals.

    View details for DOI 10.1073/pnas.1719278115

    View details for Web of Science ID 000426152500018

    View details for PubMedID 29440408

    View details for PubMedCentralID PMC5834713

  • Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ali, M., Younis, S., Wallerman, O., Gupta, R., Andersson, L., Sjoblom, T. 2015; 112 (25): 7743–48

    Abstract

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-β, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

    View details for DOI 10.1073/pnas.1509193112

    View details for Web of Science ID 000356731300067

    View details for PubMedID 26056301

    View details for PubMedCentralID PMC4485122

  • Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication SCIENCE Carneiro, M., Rubin, C., Di Palma, F., Albert, F. W., Alfoeldi, J., Barrio, A., Pielberg, G., Rafati, N., Sayyab, S., Turner-Maier, J., Younis, S., Afonso, S., Aken, B., Alves, J. M., Barrell, D., Bolet, G., Boucher, S., Burbano, H. A., Campos, R., Chang, J. L., Duranthon, V., Fontanesi, L., Garreau, H., Heiman, D., Johnson, J., Mage, R. G., Peng, Z., Queney, G., Rogel-Gaillard, C., Ruffier, M., Searle, S., Villafuerte, R., Xiong, A., Young, S., Forsberg-Nilsson, K., Good, J. M., Lander, E. S., Ferrand, N., Lindblad-Toh, K., Andersson, L. 2014; 345 (6200): 1074–79

    Abstract

    The genetic changes underlying the initial steps of animal domestication are still poorly understood. We generated a high-quality reference genome for the rabbit and compared it to resequencing data from populations of wild and domestic rabbits. We identified more than 100 selective sweeps specific to domestic rabbits but only a relatively small number of fixed (or nearly fixed) single-nucleotide polymorphisms (SNPs) for derived alleles. SNPs with marked allele frequency differences between wild and domestic rabbits were enriched for conserved noncoding sites. Enrichment analyses suggest that genes affecting brain and neuronal development have often been targeted during domestication. We propose that because of a truly complex genetic background, tame behavior in rabbits and other domestic animals evolved by shifts in allele frequencies at many loci, rather than by critical changes at only a few domestication loci.

    View details for DOI 10.1126/science.1253714

    View details for Web of Science ID 000340870900046

    View details for PubMedID 25170157

    View details for PubMedCentralID PMC5421586

  • ZBED6 Modulates the Transcription of Myogenic Genes in Mouse Myoblast Cells PLOS ONE Jiang, L., Wallerman, O., Younis, S., Rubin, C., Gilbert, E. R., Sundstrom, E., Ghazal, A., Zhang, X., Wang, L., Mikkelsen, T. S., Andersson, G., Andersson, L. 2014; 9 (4): e94187

    Abstract

    ZBED6 is a recently discovered transcription factor, unique to placental mammals, that has evolved from a domesticated DNA transposon. It acts as a repressor at the IGF2 locus. Here we show that ZBED6 acts as a transcriptional modulator in mouse myoblast cells, where more than 700 genes were differentially expressed after Zbed6-silencing. The most significantly enriched GO term was muscle protein and contractile fiber, which was consistent with increased myotube formation. Twenty small nucleolar RNAs all showed increased expression after Zbed6-silencing. The co-localization of histone marks and ZBED6 binding sites and the effect of Zbed6-silencing on distribution of histone marks was evaluated by ChIP-seq analysis. There was a strong association between ZBED6 binding sites and the H3K4me3, H3K4me2 and H3K27ac modifications, which are usually found at active promoters, but no association with the repressive mark H3K27me3. Zbed6-silencing led to increased enrichment of active marks at myogenic genes, in agreement with the RNA-seq findings. We propose that ZBED6 preferentially binds to active promoters and modulates transcriptional activity without recruiting repressive histone modifications.

    View details for DOI 10.1371/journal.pone.0094187

    View details for Web of Science ID 000334160900101

    View details for PubMedID 24714595

    View details for PubMedCentralID PMC3979763

Latest information on COVID-19