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The effects of abnormal
MEF2C activity induced by
Irregular Folic acid levels
and Notch Signaling on
Early Heart Development
Contributors: Kwame Opoku
Akyeampnog, Okhumhekho Kassim, Uyi
Jefferson Imasuen, Ali Eastman Oku
Faculty Mentor: Dr. Penny Knoblich
Department of Biological Sciences.
Hypoplastic Left Heart Syndrome
 What is Hypoplastic Left Heart Syndrome
(HLHS)?
 Phenotypes
Left ventricle underdeveloped/small
Mitral valves absent/small
Aortic valve absent/small
Ascending Aorta underdeveloped/small
Background

Cause: Unknown

Occurrence: 1 out of 4344 Babies

Different Phenotypes = Multiple Factors
Cure: ?
HLHS-Background Contd.


What genes and transcription factors are responsible for heart
development?
Relationship to notch, folic acid?
Profile of HLHS-IPS
 In HLHS-IPS there was a decrease in differentiation
potential and gene expression of Hand1, Hand2, Tbx2,
NKX2-5 and a decrease in Notch/Hey1 signaling. [9].
 MEF2C is part of the MEF2 family of transcription
factors that has a vital role in regulating gene
expression in tissues such as the heart [1]. We believe
that the malfunctioning of this regulator is responsible
for the decreased expression levels and epigenetic
modifications shown in HLHS-IPS.
Gene Regenration
Hypothesis
 During critical periods of heart development, abnormal
activity of the myocyte enhancer factor 2C (MEF2C) as a
result of irregular Notch signaling , folic acid levels,
and/or genetic mutations is the underlying cause of
HLHS.
Profile of HLHS-IPS
 Activated Notch selectively inhibits the DNA binding
and myogenic activities of MEF2C but not of other
MEF2 isoforms.( wilson Rawl)
 MEF2C also controls metalloproteinase -2 (mmp2),
which is important in cytoskeleton remodeling and
insuring the left dorsal side of the heart grows faster
than the right. (Cite)
Myotic Enhancer Factor 2C
Myotic Enhancer Factor
NOTCH Signaling
 Notch is a regulatory signaling pathway with many
receptors.
 Mutations in the Notch1 receptor.
 Paternal relationship.
NOTCH Signaling
Folic Acid Levels
A cluster of hypoplastic left heart
malformation in Baltimore, Maryland.
In the study, trichloroethylene was among
the major compounds found in most of the
implicated solvents. Studies have also shown
that trichloroethylene could cause folate
deficiencies in mammals [3].
Significance & Innovation
• Heavy genetic focus
• MEF2C & Notch 1 signaling genes
• Maternal effects on gene expression
• Genetic Mutations
• Potential change in diagnostics of HLHS
• Embryonic genetic testing
• Fetal biopsy
• Amniotic fluid analysis
• Link between MEF2C & Notch 1 signaling genes
Significance & Innovation (cont.)
• Testing
• Gene knockout analysis (siRNA and cardiac cells)
• Maternal effects on gene expression
• CRISPR-Cas 9 (very specified DNA modifications)
Acknowledgements
 Department of Biological Sciences, Minnesota
State University Mankato
 Dr. Penny Knoblich
 Katherine Campbell
 Mayo Clinic
References
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transciption actors in heart development and disease. Oxford: Academic Press.
2. Cole, C. R., & Eghtesady, P. (2016). The myocardial and coronary histopathology and pathogenesis of
hypoplastic left heart syndrome. Cardiology in the Young, 26(01), 19-29. doi:10.1017/S1047951115001171
3. Dow, J. L., & Green, T. (2000). Trichloroethylene induced vitamin B12 and folate deficiency leads to increased
formic acid excretion in the rat.Toxicology, 146(2-3), 123-136.
4. Facts about Hypoplastic Left Heart Syndrome. (2015). Retrieved January 15, 2016, from
http://www.cdc.gov/ncbddd/heartdefects/hlhs.html
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Health.5(4),219-225
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
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
Induced Pluripotent Stem Cells Identifies the Transcriptional Repression and Epigeneteic Modification of
Questions?