Heart Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 285

The chromatin-remodeling Swi/SNF-like BAF complex that is involved in cardio-
genesis is characterized by a combinatorial assembly of subunits that produces
distinct functional complexes.
In particular, the cardiogenic BAF complex comprise Swi/SNF-related, matrix-
associated, actin-dependent regulators of chromatin SMARCd1 to SMARCd3 sub-
units. 22 Cardiac-enriched BAF complex subunit SMARCd3 cooperates with GATA4
to provoke NKx2-5 production. Moreover, SMARCd3 and GATA4 cooperate with
TBx5 cardiogenic transcription factor to activate genes that encode regulators of
cardiogenesis, such as MEF2, NKx2-5, HAND, and Isl1 [ 522 ]. Factors SMARCd3,
GATA4, and TBx5 promote differentiation into contracting cardiomyocytes and
repress non-cardiac mesodermal genes.
Chromatin-remodeler and transcriptional activator SMARCa4 23 participates
in the regulation of gene expression during cardiac growth and differentiation.
The SMARCa4-containing BAF complex comprises 12 subunits. In embryos,
SMARCa4 promotes myocyte proliferation, as it maintains expression of BMP10
and suppresses that of cyclin-dependent kinase inhibitor CKI1c [ 523 ]. It interacts
with histone deacetylase and poly ADP ribose polymerase to repress α MHC (MyH6)

and activate MHC (MyH7) isoform. The chromatin-modifying HDAC-PARP-

BAF complex regulates cardiac hypertrophy. It assembles on MHC promoters,
where it can interact with transcription factors such as thyroid hormone receptors
TR

β

1 (a.k.a. nuclear receptors NR1a1 and NR1a2), transcriptional
enhancer TEA domain-containing family member TEAD1, 24 myocyte enhancer
factor MEF2, serum response factor (SRF), GATA4, and NFAT to control MHC
expression [ 523 ]. In adults, SMARCa4 is silenced in cardiomyocytes. It is
reactivated by cardiac stresses and forms a complex with its embryonic partners
HDAC and PARP1 to induce a pathological MyH6-to-MyH7 shift.
Developing myocardial cells respond to signals from the endocardial layer to
form a network of trabeculae that characterize the ventricles of vertebrate hearts.
Trabeculation requires the chromatin remodeler SMARCa4 to repress ADAM met-
allopeptidase with thrombospondin-1 motif ADAMTS1 produced in and secreted
by the endocardium that overlies developing trabeculae to achieve an extracellular
environment in the cardiac jelly that supports trabecular growth [ 524 ]. Later,
ADAMTS1 degrades the cardiac jelly and prevents excessive trabeculation.

α 1andTR β

22 A.k.a. 60-kDa Brm-associated factors (BAF60a-BAF60c) encoded by 3 genes (Baf60A-
Baf60C). Both SMARCd3a (BAF60C1) and SMARCd3b (BAF60C2) isoforms are widely
expressed [ 520 ]. These isoforms bind to several nuclear receptors and transcription factors. A
variant of the BAF complex in embryonic stem cells (esBAF) interacts with octamer-binding
transcription factor Oct4 and sex-determining region Y (SRY)-box transcription factor Sox2 [ 521 ].
Specialized chromatin-remodeling complexes exist in neural progenitors (npBAF) and neurons
(nBAF), in addition to cardiac BAF complexes (cBAF) [ 521 ].
23 A.k.a. ATP-dependent helicase brahma homolog Brg1.
24 A.k.a. transcriptional enhancer factor TEF1.