Imprinting. Joyce Ohm Cancer Genetics and Genomics CGP-L2-319 x8821

Transcription

1 Imprinting Joyce Ohm Cancer Genetics and Genomics CGP-L2-319 x8821

2 Learning Objectives 1. To understand the basic concepts of genomic imprinting Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. There are about 150 imprinted genes known in the mouse and about half that in humans. 2. To understand how genomic imprinting alters expected gene expression when compared to Mendelian inheritance patterns. Genomic imprinting is an inheritance process independent of classical Mendelian inheritance patterns. It is an epigenetic process that involves DNA methylation and chromatin remodeling without altering the genetic sequence. Epigenetic marks are established ("imprinted") in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism. 3. To appreciate the implications of genomic imprinting in human health. Appropriate imprinting of certain genes is important for normal development. Human diseases involving genomic imprinting include Angelman syndrome and Prader Willi syndrome. Imprinting and cancer

3 Mendel s Famous Peas

4 Mendel s Famous Peas

5 Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner. Some important definitions: Haploid: contains only one set of chromosomes Diploid : contains 2 sets of chromosomes Biallelic expression: a gene is expressed from both the maternal and paternal alleles. You have 2 expressed copies of the gene (Most genes) Monoallelic expression: A gene is expressed from only one of the parental alleles. You have only one expressed copy of the gene (Imprinted genes) Differentially Methylated Region (DMR): Methylated on one parental allele and not the other.

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8 Parental Conflict Theory Also known as the kinship theory of genomic imprinting: The inequality between parental genomes due to imprinting is a result of the differing interests of each parent in terms of the evolutionary fitness of their genes. The father's genes that encode for imprinting gain greater fitness through the success of the offspring, at the expense of the mother. The mother's evolutionary imperative is often to conserve resources for her own survival while providing sufficient nourishment to current and subsequent litters. Paternally expressed genes tend to be growth-promoting whereas maternally expressed genes tend to be growth-limiting.

9 Imprinted genes and development

10 Nuts and Bolts

11 Brief reminder of key regulators of active and repressed genes

12 Active Euchromatin Accessible to transcriptional activators Low density of nucleosomes H2A H2B H3 H4 H3K9ac H3K14ac H3K4me2 H3K4me3 H3K36me3 H4K16ac

13 Repressed Heterochromatin Densely packed nucleosomes X Transcriptionally inaccessible H2A H2B H3 H4 H3K27me2 H3K27me3 H3K9me H3K9me2 H3K9me3 DNA methylation

14 CTCF

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16 Genomic imprinting is just monoallelic gene silencing inherited in a parent of origin specific fashion

17 Imprinting control region (ICR) Regulatory elements which control imprinting of one or more genes. Differentially methylated regions of DNA rich in cytosine and guanine nucleotides Hemi-methylated: cytosine nucleotides methylated on one copy but not on the other. Associate with non-coding RNAs to recruit CTCF and are essential for imprinting of genes in their corresponding regions.

18 Methylation Cytosine 5-Methylcytosine DNA methyltransferase S-adenosyl methionine See Dr. Smiraglia s Lecture from last week

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20 lncrna as a regulator of chromatin complex remodeling CTCF

21 Putting it all together

22 Imprint acquisition and erasure in mammalian development Imprints are present in gametes Imprint maintained after fertilization Imprintes ERASED in gonad before sex determination Imprints are acquired by gametes The parental alleles are differentially marked by DNA methylation during gametogenesis when the genomes are in separate compartments. This is how the methylation machinery distinguished the paternal vs. maternal allele.

23 Model for the establishment of male germline imprinting marks. The Journal of Pathology Volume 211, Issue 3, pages , 18 DEC 2006 DOI: /path

24 Real world consequences

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26 Angelman s syndrome Prader Willi Syndrome start at 3:50:

27 Chromosome 15 region that controls PWS and AS

28 Chromosome 15 region that controls PWS and AS DNA methylation? lncrna? CTCF?

29 Genomic imprinting in cancer

30 Loss of imprinting (LOI) of the Igf2/H19 loci has been linked to colon cancer Loss of Imprinting (LOI) of the Igf2 gene correlates with colon cancer Result= Maternal Igf2 gene is turned on With family history- 5X more likely to show LOI Polyps detected- 3X more likely to show LOI Personal history- 22X more likely to show LOI

31 Other links Mice engineered to be imprintfree are tumor prone Normal imprinting of some genes is disrupted in tumors PEG1 in lung cancer TP73 in gastric cancer CDKN1C in pancreatic cancer IGF2 in Beckwith-Wiedemann Syndrome(BWS): a cancer predisposition syndrome results from abnormal expression of imprinted genes on chromosome 11 Wilms tumor Adrenocortical carcinoma Rhabdomysarcoma Hepatoblastoma Hepatocellular carcinoma Breast cancer Lung cancer Colorectal cancer Leiomyosarcoma Testicular germ cell cancer Renal cell carcinoma Kidney clear cell carcinoma Choriocarcinoma Cervical carcinoma Oesophageal cancer AML

32 Beckwith-Wiedemann Syndrome (BWS) Overgrowth and cancer predisposition syndrome fold increased risk to specific embryonal tumors (i.e. Wilms tumor) Enlarged tongue (macroglossia) Enlarged kidneys Enlarged pancreas Other developmental defects Imbalance in the expression of one or more 11p15.5 imprinted genes (contains both the IGF2/H19 cluster and the KvDMR1 cluster) Main causes: Over-activity of IGF2 / loss of CDKN1C expression >50% of cases due to abnormal DNA methylation

33 Imprinted genes and cancer?