Phosphorylation of the Twist1-Family Basic Helix-Loop-Helix Transcription Factors Is Involved in Pathological Cardiac Remodeling

Abstract

BackgroundThe Twist1-family basic helix-loop-helix (bHLH) transcription factors including Twist1, Hand1 and Hand2, play an essential role in heart development and are implicated in pathological heart remodeling. Previously, it was reported that these bHLH transcription factors can be regulated by phosphorylation within the basic-helix I domain, which is involved in developmental processes such as limb formation and trophoblast differentiation. However, how phosphorylation of Twist1 family functions in post-natal heart is elusive.Principal FindingsHere, we generated transgenic mice with over-expression of Hand1 and Twist1 mutants (to mimic or to abolish phosphorylation) in cardiomyocytes and found pathological cardiac remodeling leading to heart failure and sudden death. Gene expression profile analysis revealed up-regulation of growth-promoting genes and down-regulation of metabolic genes. It is well known that aberrant activation of Akt signaling causes pathological cardiac remodeling and results in heart failure. The basic-helix I domain of Twist1 family members contain Akt substrate consensus motif and may be downstream targets of Akt signaling. Using biochemical analysis, we demonstrated that Hand1 and Twist1 were phosphorylated by Akt in the basic-helix I domain. Phosphorylation of Hand1 regulated its transcriptional activation of luciferase reporter genes and DNA binding ability.ConclusionsThis study provides novel insights into the regulation of Twist1 family in cardiac remodeling and suggests that the Twist1 family can be regulated by Akt signaling.

Phosphorylation of basic helix–loop–helix transcription factor Twist in development and disease

“…The mice expressing the Twist1 mutant undergo hypertrophy and show atrial and ventricular septal defects, which are not seen in mice expressing wild-type Twist1. This is very similar to the observations in mice expressing a non-phosphorylatable Hand1 mutant, another member of the Twist transcription factor family, which also show a significant hypertrophy phenotype in the first month after birth, and die after 2 months [17].…”

“…This implies a high possibility that these two residues can be phosphorylated by PKB, probably in a context-dependent manner. Indeed, both residues can be phosphorylated by activated PKB [17]. By using transgenic mice that overexpress an unphosphorylatable mutant of Twist1 specifically in cardiomyocytes, postnatal development of heart function is severely interrupted.…”

Identification of Temporal and Region-Specific Myocardial Gene Expression Patterns in Response to Infarction in Swine

“…The Twist family of basic helix-loop-helix (bHLH) transcription factors including TWIST1/2, HAND1/2, Scleraxis, and Paraxis, play a variety of roles in both embryonic development and diseases [51]–[53]. A study performed with transgenic mice overexpressing HAND1 and TWIST1 in cardiomyocytes reported pathological cardiac remodelling leading to HF and sudden death [54]. On the other hand, PPARD is a critical regulator of fatty acid oxidation in cardiac tissue and its lack of expression has been associated with the onset of cardiac failure [55].…”

Post-translational modifications of EMT transcriptional factors in cancer metastasis

“…This modification was required for inhibiting p53 as well as promoting cell survival after DNA damageinduced stress [45]. Besides, phosphorylation of basichelix I motif by Akt was critical for Twist to cooperated with Hand1 in the regulation of cardiac remodeling [46]. Therefore, Twist phosphorylation may be involved in the cellular programming and development other than cancer metastasis.…”