Unit 2 Pathphysiology - Chapter 6 Epigenetics and Disease

Question 1

3 major epigenetic processes

Overview of Epigenetic Mechanisms

Answer 1

• DNA methylation: attachment of a methyl group to a cytosine; in somatic cells, all or nearly all methylation occurs at cytosines binded with guanines
  When gene heavily methylated, DNA less likely to transcribe into mRNA
• HIstone modification: methylation and acetylation most studied

HIstones => bind to DNA, modify chromatin shape and regulate activity of genes
Histone acetylation remove positve charge of histones => reduce their binding strength to negatively charged DNA => more DNA accessible for transcription (Acetylating the histone reduces how tightly DNA is wrapped around the nucleosome, thus allowing transcription machinery to more easily enter)
BONUS — HIstone methylation can either strengthen or weaken bonding between DNA and histones

• noncoding RNAs (ncRNAs or miRNAs or microRNAs): from introns of protein coding genes or transcribed as independent genes from regions of genome with unknown functions; microRNAs regulate diverse signaling pathways

Question 2

When twins age, what happens to their phenotypes?

Overview of Epigenetic Mechanisms

Answer 2

Due to aging, there are differences in methylation patterns of DNA l/t increased # of phenotypic differences.

Question 3

Transcriptionally active versus inactive (gene silencing)

Genomic Imprinting

Answer 3

A given gene (either from father or mother it is designated) is only transcriptionally active on one copy of a chromosome; on other copy (determined by other precondition whether it be father or mother) is transcriptionally inactive

depends on who transmit gene will determine which gene will be silnced; the silenced gene is “imprinted”

Question 4

What is different about an imprinted allele

Genomic Imprinting

Answer 4

dense w/ DNA methylation; nonimprinted allele is not methylated

Humans inherit two alleles from mother and father, both are functional for the majority of the genes, but sometimes one is turned off or “stamped” and doesn’t show in offspring, that gene is imprinted. Imprinting means that that gene is silenced, and gene from other parent is expressed.

Question 5

Prader-Willi syndrome

Genomic Imprinting

Answer 5

deletion of approximately 4 million Mb or base pairs of long arm (chromosome 15); when father inherits it then child will manifest it

• early infancy: hypotonia, poor appetite, feeding difficulties
• early childhood: excessive eating and gradual morbid obesity (unless controlled intake)
• motor milestones and language devlopment - delayed

Question 6

Angelman syndrome

Genomic Imprinting

Answer 6

same 4-Mb deletion as prader-willi syndrome when inherited by mother

• delayed development
• intellectual disability
• severe speech impairment
• ataxia (impaired mvmt and balance)

Question 7

Beckwith-Wiedemann syndrome

Genomic Imprinting

Answer 7

overgrowth condition (r/t imprinting) accompanied by an increased predisposition to cancer // upregulation of active IGF2 (growth factor 2) causes this overgrowth

• large body size @ birth, large tongue, hypoglycemia
• taller than avg height during childhood

Question 8

Russell-silver syndrome

Answer 8

intrauterine growth restriction; downregulation of IGF2 causes diminished growth

• poor growth after birth
• large head, traingle facial appearance, prominent forehead
• body assymmetry
• significant feeding difficulties

Question 9

Alcohol during pregnancy

Epigenetics in Cognitive Development and Mental Health

Answer 9

Fetal alcohol syndrome (cognitive abnormalities) via altered methylation of genes invovled in neuronal differentiation

• FAS ^^^^^^
• low body weight, poor coordination, hyperactive
• poor attention, memory
• learning disability
• speech + lang delay

Question 10

Do people with autism, PTSD have altered DNA methylation profiles?

Epigenetics in Cognitive Development and Mental Health

Answer 10

yes

Question 11

Fragile X syndrome

Epigenetics in Cognitive Development and Mental Health

Answer 11

interaction (genetic & epigenetic abnormalities) + a lot of methylation

• cognitive impairment, learning disabilities
• delayed milestones, gestures + body language as well
• math and language delay
• male more severely affected; usually by age 2

Question 12

Facioscapulohumeral muscular dystrophy (FSHD)

Answer 12

caused by abnormal loss of methylation

• teen years (noticible in infancy)
• muscle weakness and wasting (atrophy)
• face, shoulder blades, and upper arms
• less recognized - hamstring and trunk + other limbs
• slow progression
• autosomal dominant genetic condition

Question 13

Can identical twins diverge epigenetically

Epigenetic Change over the Life Span

Answer 13

Yes through enviornmental factors such as tobacco use

Question 14

What can metformin do?

Epigenetic Change over the Life Span

Answer 14

Prolong life through epigenetic mechanisms

Question 15

Bisulfite conversion

Epigenetic Change over the Life Span

Answer 15

makes changes to cytosine and methylcytosine in terms of binding properties, to be distingushed in sequence data

Question 16

Assay for transposase-accessible chromatin (ATAC-seq)

Epigenetic Change over the Life Span

Answer 16

uses tranposase to introduce DNA cell-specific barcodes into euchromatic (looser) DNA regions alllowing comparison between cells

Question 17

What happens when tumors progress?

Epigenetics and Cancer

Answer 17

methylation densities decrease when tumors grow => oncogenes increase causing benign neoplasm to progress to malignancy

promotor regions of tumor-suppressor genes often hypermethylated; decreased their transcription

Question 18

How about microRNA and hypermethylation?

Epigenetics and Cancer

Answer 18

tumorigenesis

Question 19

5-Azacytidine

Epigenetics and Cancer

Answer 19

demethylating agent; therapeutic agent used in leukemia and myelodysplastic syndrome // cytosine analog that is refractory to methyl group additions => address methylation densities (other diseases)

• leukemia: white blood cells (blood cancer)
• Myelodysplastic syndrome: bone marrow unable to produce normal evels of one or more type of blood cell (bleeding, anemia, recurrent infection)

Question 20

Histone-deacetylase inhibitors

Emerging Strategies for the Treatment of Epigenetic Disease

Answer 20

Promise in txing breast, prostate, and pancreas

Question 21

Uniparental disomy

Answer 21

Minority of Beckwith-Wiedemann syndrome cases (as w/ angelman syndrome) [around 20%-30%] are casued by inheritance of two copie of chromosome 11 from the father and none form mother

overexpression of gene product

Question 22

Housekeeping genes

Answer 22

necessary for maintenance/fx of cells; escape silencing and remain transcriptionally active; encode histones, DNA, and RNA polymerases, and rRNA genes

Question 23

DNA methyltransfereases

Answer 23

follow replcation, methyltransferease read pattern of methylation on parent DNA strand and use that info to determine daughter-strand cytosines should be methylated, as cell division proceedes then all cells have loci unmethylated

during implantation in uterus, DNA methyltransferease becomes active again permitting cell lineage-specific marks for organ systems