TBX5: A Key Regulator of Heart Development

Abstract

TBX5 is a member of the T-box transcription factor family and is primarily known for its role in cardiac and forelimb development. Human patients with dominant mutations in TBX5 are characterized by Holt-Oram syndrome, and show defects of the cardiac septa, cardiac conduction system, and the anterior forelimb. The range of cardiac defects associated with TBX5 mutations in humans suggests multiple roles for the transcription factor in cardiac development and function. Animal models demonstrate similar defects and have provided a useful platform for investigating the roles of TBX5 during embryonic development. During early cardiac development, TBX5 appears to act primarily as a transcriptional activator of genes associated with cardiomyocyte maturation and upstream of morphological signals for septation. During later cardiac development, TBX5 is required for patterning of the cardiac conduction system and maintenance of mature cardiomyocyte function. A comprehensive understanding of the integral roles of TBX5 throughout cardiac development and adult life will be critical for understanding human cardiac morphology and function.

Keywords: Cardiac development; Cardiac morphogenesis; Holt–Oram syndrome; TBX5; Transcriptional regulation.

Fig. 1

Representation of Tbx5 regulatory domain. Chromatin capture techniques suggest interactions between the promoter of Tbx5 and cis-regulatory elements are limited to a 375-kbp region demarcated by functional CTCF sites located between Rbm19 and Tbx5 and Tbx5 and Tbx3 (van Weerd et al., 2014).

Fig. 2

Transcriptional regulation by TBX5. TBX5, through its interactions with other cardiac transcription factors, such as GATA4 and NKX2-5, and the BAF chromatin-remodeling complex drive active transcription of target cardiac genes in regions of open chromatin (top panel). TBX5, through its interactions with the NuRD complex and other transcriptional repressors, such as SALL4, remodel chromatin to a closed state, which represses gene expression of noncardiac genes (bottom panel). Reprinted from Boogerd, C. J., & Evans, S. M. (2016). TBX5 and NuRD divide the heart. Developmental Cell, 36(3), 242–244, with permission from Elsevier.