1 Day Date Subject To be read prior to this class period: Th3/12Chapter 7 T3/17 students = epigenetics Richie Th3/19students = toxicology and cancer Anna, Bouradee T3/24 Th3/26 T3/31no class - Spring Break Th4/2no class - Spring Break T4/7students = life cycles Th4/9 Chapter 9 second short writing assignment due at the start of class on Thurs, 4/9 T4/14students = nutrients and development Meg, Zeb Th4/16 T4/21students = evolution Greg Th4/23Chapter 10 T4/28 Th4/30Capstone Papers due Chapter 8 T5/5Discussion of Capstone Papers Th5/7Chapter 8 Comprehensive Final Exam, Thursday, May 7 th, 8:00 – 10:00 AM

2 second short writing assignment for your Capstone project: 1)Describe your career goals. 2)Describe you past, current, and future career plans and efforts. 3) Explain which college course has had the most impact on your career plans and why (not this class). 4) Connect your career goals, plans, and efforts with your Capstone project efforts in as many ways as you can. These can be similarities and/or differences. 5) What kind of sources/references could be include in this writing? Incorporate at least five sources/references.

3 toxicology and cancer epigenetics

4 epigenetics (narrow definition) = DNA methylation and/or histone modification DNA methylation stories: 1) promoter of the glucocorticoid receptor 2) thrifty phenotype in mammmals 3) folic acid (methyl donor) in obesity of agouti rats 4) queen ants 5) transgenerational 6) Richie’s paper on the “methylome” imprinting embryonic stem cells

In the promoter for the glucocorticoid receptor

6 I Googled: glucocorticoid receptor DNA methylation brain

7 epigenetics (narrow definition) = DNA methylation and/or histone modification DNA methylation stories: 1) promoter of the glucocorticoid receptor 2) thrify phenotype in mammmals 3) folic acid (methyl donor) in obesity of agouti rats 4) queen ants 5) transgenerational 6) Richie’s paper on the “methylome” imprinting embryonic stem cells

8 There are many examples of maladaptive responses in Chapter 7 plus new examples that aren’t maladaptive. maladaptive = a misinterpretation of the environment Dutch Hunger Winter

9 There are many examples of maladaptive responses in Chapter 7 plus new examples that aren’t maladaptive. maladaptive = a misinterpretation of the environment Dutch Hunger Winter The thrifty phenotype hypothesis is a example of a Predictive Adaptive Response. All the examples from the first third of the course were PARs.

10 There are many examples of maladaptive responses in Chapter 7 plus new examples that aren’t maladaptive. maladaptive = a misinterpretation of the environment Dutch Hunger Winter

11 correlation of adult blood pressure and birth rate:

12 Molecular mechanism might be in the kidney?

13 thrifty phenotype in mammals KIDNEY: Poor nutrition during fetal life reduces the number of nephrons predisposing the person to high blood pressure later in life. PANCREAS: Poor nutrition during fetal life reduces the number of insulin-secreting cells predisposing the person to type 2 diabetes later in life. LIVER: Poor nutrition during fetal life changes histology and gene expression of the liver. One result is that more glucose is made and less is degraded.

14 Thrifty Phenotype Hypothesis: Malnourished fetuses are “programmed” to expect poor nutrients postnatally and set their biochemical parameters to conserve energy and store fat.

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16 Thrifty Phenotype Hypothesis: Malnourished fetuses are “programmed” to expect poor nutrients postnatally and set their biochemical parameters to conserve energy and store fat. The thrifty phenotype appears to be triggered by either poor nutrients or stress. (???)

17 epigenetics (narrow definition) = DNA methylation and/or histone modification DNA methylation stories: 1) promoter of the glucocorticoid receptor 2) thrifty phenotype in mammmals 3) folic acid (methyl donor) in obesity of agouti rats 4) queen ants 5) transgenerational 6) Richie’s paper on the “methylome” imprinting embryonic stem cells

Environment can affect phenotype. Environment = nutrients = folic acid (a methyl donor) Phenotype = fur color and obesity Plasticity caused by = methylation patterns of the agouti gene Reaction Norm

19 epigenetics (narrow definition) = DNA methylation and/or histone modification DNA methylation stories: 1) promoter of the glucocorticoid receptor 2) thrifty phenotype in mammmals 3) folic acid (methyl donor) in obesity of agouti rats 4) queen ants 5) transgenerational 6) Richie’s paper on the “methylome” imprinting embryonic stem cells

20 The environment (nutrients in the form of ‘royal jelly’) acts to increase hormones (juvenile hormone + insulin signaling) and their effects include decreased DNA methylation, which increases expression of genes needed to form queens. EXPERIMENT: When fed methylation inhibitors, larvae develop into queens.

21 epigenetics (narrow definition) = DNA methylation and/or histone modification DNA methylation stories: 1) promoter of the glucocorticoid receptor 2) thrifty phenotype in mammmals 3) folic acid (methyl donor) in obesity of agouti rats 4) queen ants 5) transgenerational 6) Richie’s paper on the “methylome” imprinting embryonic stem cells

22 Definition from Genetics: allele = one version of a gene. chromatin = DNA plus associated proteins. Chromosomes are composed of chromatin. Looking ahead to Chapter 10: Altered chromatin can be inherited and is called an epiallele.

Pregnant rats fed a low-protein diet have offspring predisposed to obesity. In Chapter 7, there are changes in DNA methylation on the PPARalpha and Dnmt1 genes (involved in fat production). Transgenerational Multigenerational We have had examples of maladaptive responses that involve DNA methylation:

24 epigenetics (narrow definition) = DNA methylation and/or histone modification DNA methylation stories: 1) promoter of the glucocorticoid receptor 2) thrifty phenotype in mammmals 3) folic acid (methyl donor) in obesity of agouti rats 4) queen ants 5) transgenerational 6) Richie’s paper on the “methylome” imprinting embryonic stem cells

25 research article Richie selected

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11.5 germ cell migration

32 In primordial germ cells (PGCs) representing the precursors of SSCs and all other germ cells, the genome is demethylated and, in particular, the genomic imprints, i.e. the parent-specific methylation marks of imprinted genes, of the previous generation are erased from the grandparental chromosomes (with respect to the new embryo). In the mouse, this wave of genome-wide epigenetic reprogramming starts between day 10.5 post conceptionem (p.c.) before migration of PGCs into the genital ridge and is completed by day 13.5 p.c. (Hajkova et al., 2002; Yamazaki et al., 2003). In the male germline, the establishment of novel methylation marks for imprinted genes begins around day 15.5 p.c., but is finished only after birth (Davis et al., 1999, 2000; Li et al., 2004). After fertilization, a second wave of genome-wide epigenetic reprogramming takes place in which the vast majority of male and female germline-derived methylation patterns are erased again and new somatic methylation patterns for development of the new organism are established (Mayer et al., 2000a, b). To the extent of present knowledge, imprinted genes escape this second wave and maintain their germline-specific methylation and parent-specific expression patterns throughout further development (Morgan et al., 2005). Thus, imprinted genes display a differential methylation of their parental alleles and maintenance of genomic imprinting in both ESCs and somatic cells. In contrast, pluripotency marker genes such as Oct4 and Nanog switch from a transcriptionally active and demethylated state in ESCs to a transcriptionally repressed and fully methylated state in somatic cells (Okita et al., 2007; Wernig et al., 2007).

33 In primordial germ cells (PGCs) representing the precursors of SSCs and all other germ cells, the genome is demethylated and, in particular, the genomic imprints, i.e. the parent-specific methylation marks of imprinted genes, of the previous generation are erased from the grandparental chromosomes (with respect to the new embryo).

34 In primordial germ cells (PGCs) representing the precursors of SSCs and all other germ cells, the genome is demethylated and, in particular, the genomic imprints, i.e. the parent-specific methylation marks of imprinted genes, of the previous generation are erased from the grandparental chromosomes (with respect to the new embryo). In the mouse, this wave of genome-wide epigenetic reprogramming starts between day 10.5 post conceptionem (p.c.) before migration of PGCs into the genital ridge and is completed by day 13.5 p.c. (Hajkova et al., 2002; Yamazaki et al., 2003).

35 In primordial germ cells (PGCs) representing the precursors of SSCs and all other germ cells, the genome is demethylated and, in particular, the genomic imprints, i.e. the parent-specific methylation marks of imprinted genes, of the previous generation are erased from the grandparental chromosomes (with respect to the new embryo). In the mouse, this wave of genome-wide epigenetic reprogramming starts between day 10.5 post conceptionem (p.c.) before migration of PGCs into the genital ridge and is completed by day 13.5 p.c. (Hajkova et al., 2002; Yamazaki et al., 2003). In the male germline, the establishment of novel methylation marks for imprinted genes begins around day 15.5 p.c., but is finished only after birth (Davis et al., 1999, 2000; Li et al., 2004). After fertilization, a second wave of genome-wide epigenetic reprogramming takes place in which the vast majority of male and female germline-derived methylation patterns are erased again and new somatic methylation patterns for development of the new organism are established (Mayer et al., 2000a, b). To the extent of present knowledge, imprinted genes escape this second wave and maintain their germline-specific methylation and parent-specific expression patterns throughout further development (Morgan et al., 2005). Thus, imprinted genes display a differential methylation of their parental alleles and maintenance of genomic imprinting in both ESCs and somatic cells. In contrast, pluripotency marker genes such as Oct4 and Nanog switch from a transcriptionally active and demethylated state in ESCs to a transcriptionally repressed and fully methylated state in somatic cells (Okita et al., 2007; Wernig et al., 2007).

36 In primordial germ cells (PGCs) representing the precursors of SSCs and all other germ cells, the genome is demethylated and, in particular, the genomic imprints, i.e. the parent-specific methylation marks of imprinted genes, of the previous generation are erased from the grandparental chromosomes (with respect to the new embryo). In the mouse, this wave of genome-wide epigenetic reprogramming starts between day 10.5 post conceptionem (p.c.) before migration of PGCs into the genital ridge and is completed by day 13.5 p.c. (Hajkova et al., 2002; Yamazaki et al., 2003). In the male germline, the establishment of novel methylation marks for imprinted genes begins around day 15.5 p.c., but is finished only after birth (Davis et al., 1999, 2000; Li et al., 2004). After fertilization, a second wave of genome-wide epigenetic reprogramming takes place in which the vast majority of male and female germline-derived methylation patterns are erased again and new somatic methylation patterns for development of the new organism are established (Mayer et al., 2000a, b). To the extent of present knowledge, imprinted genes escape this second wave and maintain their germline-specific methylation and parent-specific expression patterns throughout further development (Morgan et al., 2005). Thus, imprinted genes display a differential methylation of their parental alleles and maintenance of genomic imprinting in both ESCs and somatic cells. In contrast, pluripotency marker genes such as Oct4 and Nanog switch from a transcriptionally active and demethylated state in ESCs to a transcriptionally repressed and fully methylated state in somatic cells (Okita et al., 2007; Wernig et al., 2007).