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Abstract MP115: Transcriptional Patterning of the Ventricular Cardiac Conduction System
Abstract only The heart beats 2 billion times over the average human lifespan and is the manifestation of a pattern of cardiomyocyte depolarization organized by a specialized network of cardiomyocytes, the cardiac conduction system (CCS). Patterning of the CCS into atrial node versus ventricular con...
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Published in: | Circulation research 2020-07, Vol.127 (Suppl_1) |
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Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Abstract only
The heart beats 2 billion times over the average human lifespan and is the manifestation of a pattern of cardiomyocyte depolarization organized by a specialized network of cardiomyocytes, the cardiac conduction system (CCS). Patterning of the CCS into atrial node versus ventricular conduction system (VCS) components with distinct physiology is essential for the normal heartbeat and has been recognized for more than a century. However molecular basis of this regional patterning is not well understood. Using mouse genetics, we found that the ratio between T-box transcriptional activator,
Tbx5
, and T-box transcriptional repressor,
Tbx3
, determines the molecular and functional output of VCS myocytes. Adult VCS-specific removal of
Tbx5
or overexpression of
Tbx3
re-patterned the fast VCS into slow, nodal-like cells based on molecular, cellular and functional criteria. Specifically, the ventricular fast conduction gene expression network was lost whereas the slow conduction nodal gene expression network was retained. Action potentials (APs) of
Tbx5
-deficient VCS myocytes adopted nodal-specific characteristics, including increased AP duration and cellular automaticity. Removal of
Tbx5 in-vivo
precipitated inappropriate depolarizations in the His-bundle that initiated lethal ventricular arrhythmias. A T-box rheostat mechanism for CCS patterning was confirmed by
Tbx5/Tbx3
genetic interaction studies. TBX5 bound and directly activated
cis
-regulatory elements at fast conduction loci genome-wide, defining the identity of the adult VCS. Furthermore, TBX5 bound and activated cis-regulatory elements at
Tbx5
itself, describing a multi-tiered T-box-dependent fast conduction gene regulatory network (GRN). The hierarchical GRN established a bi-stable network in mathematical modeling, with only high or low fast conduction gene expression states, suggesting a genomic mechanism for the establishment of VCS versus nodal states
in-vivo
. Thus, the CCS is patterned entirely as a slow, nodal ground state, with a T-box dependent, physiologically dominant, fast conduction network driven specifically in the VCS. Disruption of the fast VCS GRN allowed nodal physiology to emerge, providing a molecular mechanism for some lethal ventricular arrhythmias. |
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ISSN: | 0009-7330 1524-4571 |
DOI: | 10.1161/res.127.suppl_1.MP115 |