# Ancestral roles of histone-modifying genes in heart development and disease

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $772,500

## Abstract

Project Summary  Large numbers of gene variants were identified from genomic sequencing of Congenital Heart Disease  patients,  but  lack  of  functional  verification  in  heart  development  precludes  assigning  “disease  gene”  status.  Genetic  control  of  heart  development  is  conserved  from  Drosophila  to  humans,  thus  investigations  in  flies  can  illuminate  gene  functions  in  human  heart  development  and  disease.  We  developed  a  gene  validation  system  in  Drosophila  to  screen  large  numbers  of  genes  for  roles  in  heart  development,  and  quantitative  analysis  tools  to  assess  multiple  phenotypic  parameters.  We  also  developed  novel  strategies  to  test  patient-¬derived  genetic  mutations  in  flies  for  in  vivo  evidence  linking  specific  gene  variants  to  disease.  We  observed  that  many  histone modifying  genes  mutated  in  disease  patients have roles in fly heart development. We propose studies designed to elucidate ancestral roles of  histone-¬modifying  genes  in  heart  development  and  disease,  and  to  generate  personalized  fly  heart  disease models for specific gene variants. Using the high-throughput Drosophila gene validation screen  for  essential  roles  in  heart  development,  we  will  test  candidate  disease  genes  identified  from  publicly  available  datasets  and  collaborators’  unpublished  datasets.  We  will  also  screen  Drosophila  genes  encoding enzymes for histone methylation/demethylation and acetylation/deacetylation for roles in heart  development.  Histone  modifying  genes  validated  by  screening  will  be  phenotyped  using  multiple  quantifiable  morphological  and  functional  readouts.  We  will  identify  histone  modifications  that  are  most  important  for  heart  development.  Genes  will  be  prioritized  based  on  multiple  criteria,  and  for  highest  priority  genes  we  will  examine  the  transcriptional  profile  of  heart  tissue  from  flies  in  which  the  gene  of  interest was silenced in cardiac cells. We will identify conserved targets of histone modification effects by  comparing  our  results  to  data  from  murine  models  and  patient  tissue  samples.  We  will  generate  transgenic and knock-in fly models to provide in vivo functional evidence for involvement of high priority  gene  variants  in  congenital  heart  disease.  In  pReplacement,  we  will  express  wild  type  or  mutant  transgene  versions  of  a  given  human  disease  gene  in  the  fly  heart  while  simultaneously  silencing  the  endogenous  fly  homolog.  We  will  also  generate  “knock-in”  Drosophila  models  using  CRISPR/Cas9-mediated  gene  editing.  In  this  pCRISPR  approach,  the  endogenous  Drosophila  homolog  is  precisely  modified to encode a protein with amino acid changes identical to those encoded in the patient-¬derived  mutant allele. We will also use Drosophila to model polygenic disease based on selected patients...

## Key facts

- **NIH application ID:** 9991888
- **Project number:** 5R01HL134940-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** ZHE HAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $772,500
- **Award type:** 5
- **Project period:** 2019-07-22 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991888

## Citation

> US National Institutes of Health, RePORTER application 9991888, Ancestral roles of histone-modifying genes in heart development and disease (5R01HL134940-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9991888. Licensed CC0.

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