Epigenetics of HF

Question 1

Epigenetics definition

Answer 1

non-genetic changes that alter gene expression without affecting the DNA sequence itself

Question 2

Basic epigenetic mechanisms

Answer 2

• Enzymatic post-translational modification of Lysine residues on histone tails
  
  • Acetylation / deacetylation
  • Plus a wide variety of other modifications
• ATP-dependent chromatin remodeling enzymesChromatin binding proteins
• Chromatin binding proteins

Question 3

“histone code” definition

Answer 3

• pattern of chromatin modification that is read by different proteins which have specific domains that bind modified histones
• ultimately controls whether or not RNA pol II can gain access to gene promoters to affect gene transcription

Question 4

acetylation/deacetylation impact on transcription

Answer 4

Generally, acetylation promotes gene expression and deacetylation inhibits gene expression

Question 5

Molecular hallmarks of cardiac hypertrophy

Answer 5

• biomarkers: ANF and BNP are protein biomarkers not expressed in the healthy heart
• New protein synthesis
• New sarcomere assembly
• Gene expression

Question 6

Epigenetic influences (specific enzymes) on pathological hypertrophy

Answer 6

• HDAC9 (histone deacytelase 9)
• HDAC1/2 (histone deacytelase 1/2)

Question 7

Impact of HDAC9 on pathological cardiac hypertrophy

Answer 7

• Overexpression of HDAC9 blocks cardiomyocyte hypertrophy
• Knockout stimulates cardiomyocyte hypertrophy; also stimulates expression of BNP, a biomarker of pathological hypertrophy
• Upshot: HDAC suppresses hypertrophy in response to stress by deacetylating (“turning off”) genes required for hypertrophic growth

Question 8

Impact of HDAC1/2 on pathalogical cardiac hypertrophy

Answer 8

• Deacetylates genes that suppress growth –> allows heart to grow in response to stress
• HDAC1/2 inhibitors promising drug candidates for treatment of heart failure