Mapping and rewiring the MYBPC3 promoter for rescue of haploinsufficiency driven hypertrophic cardiomyopathy

Abstract

Autosomal dominant loss-of-function variants in the gene MYBPC3 are, collectively, the most common genetic cause of hypertrophic cardiomyopathy (HCM) and are a prototype of haploinsufficient human disease. Typical for haploinsufficiency-associated genes, hundreds of unique loss-of-function pathogenic variants have been reported for MYBPC3 - therapeutic gene editing to correct each of these variants poses major regulatory and logistical hurdles. Upregulating wild-type allele expression could offer a generalizable therapeutic strategy, but the capacity to modulate native MYBPC3 transcription is unknown. Here, we present a variant-agnostic approach to rescue haploinsufficiency by mapping and rationally redesigning the MYBPC3 promoter. Using massively parallel reporter assays (MPRAs) in human induced pluripotent stem cell-derived cardiomyocytes, we performed saturation mutagenesis of the MYBPC3 promoter at single base-pair resolution. This defined a new class of clinically relevant noncoding loss-of-function variants while revealing essential cis-regulatory grammar anchored by key transcription factor binding sites (TFBSs). Furthermore, by systematically screening thousands of variant combinations, modular promoter elements, and heterologous TFBS insertions, we identified synergistic sequence edits that drive robust increases in MYBPC3 expression. Together, our findings improve the clinical interpretation of noncoding variants and establish a scalable blueprint for promoter editing to treat MYBPC3-associated HCM and other haploinsufficient diseases.

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BibTeX RIS

BibTeX

@misc{renberg2026mapping,
  title = {{Mapping and rewiring the MYBPC3 promoter for rescue of haploinsufficiency driven hypertrophic cardiomyopathy}},
  author = {A. Renberg and S. Coppersmith and O. Merritt and Y.-C. Tsan and E. Ismail and J. Licata and M. U. Sheth and R. Gupta and A. Kundaje and S. Friedline and H. Helms and E. D. Hughes and Z. T. Freeman and G. Powell and J. S. Ware and J. Meisner and E. Smith and A. Tovar and J. Engreitz and J. O. Kitzman and A. S. Helms},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.20.752987},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.20.752987v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Mapping and rewiring the MYBPC3 promoter for rescue of haploinsufficiency driven hypertrophic cardiomyopathy
AU  - A. Renberg
AU  - S. Coppersmith
AU  - O. Merritt
AU  - Y.-C. Tsan
AU  - E. Ismail
AU  - J. Licata
AU  - M. U. Sheth
AU  - R. Gupta
AU  - A. Kundaje
AU  - S. Friedline
AU  - H. Helms
AU  - E. D. Hughes
AU  - Z. T. Freeman
AU  - G. Powell
AU  - J. S. Ware
AU  - J. Meisner
AU  - E. Smith
AU  - A. Tovar
AU  - J. Engreitz
AU  - J. O. Kitzman
AU  - A. S. Helms
PY  - 2026
DA  - 2026/09/20
PB  - bioRxiv
DO  - 10.64898/2026.09.20.752987
UR  - https://www.biorxiv.org/content/10.64898/2026.09.20.752987v1
AB  - Autosomal dominant loss-of-function variants in the gene MYBPC3 are, collectively, the most common genetic cause of hypertrophic cardiomyopathy (HCM) and are a prototype of haploinsufficient human disease. Typical for haploinsufficiency-associated genes, hundreds of unique loss-of-function pathogenic variants have been reported for MYBPC3 - therapeutic gene editing to correct each of these variants poses major regulatory and logistical hurdles. Upregulating wild-type allele expression could offer a generalizable therapeutic strategy, but the capacity to modulate native MYBPC3 transcription is unknown. Here, we present a variant-agnostic approach to rescue haploinsufficiency by mapping and rationally redesigning the MYBPC3 promoter. Using massively parallel reporter assays (MPRAs) in human induced pluripotent stem cell-derived cardiomyocytes, we performed saturation mutagenesis of the MYBPC3 promoter at single base-pair resolution. This defined a new class of clinically relevant noncoding loss-of-function variants while revealing essential cis-regulatory grammar anchored by key transcription factor binding sites (TFBSs). Furthermore, by systematically screening thousands of variant combinations, modular promoter elements, and heterologous TFBS insertions, we identified synergistic sequence edits that drive robust increases in MYBPC3 expression. Together, our findings improve the clinical interpretation of noncoding variants and establish a scalable blueprint for promoter editing to treat MYBPC3-associated HCM and other haploinsufficient diseases.
ER  -

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