SALL4 controls cell fate in response to DNA base composition

Abstract

<jats:title>Abstract</jats:title><jats:p>Mammalian genomes contain long domains with distinct average compositions of A/T versus G/C base pairs. In a screen for proteins that might interpret base composition by binding to AT-rich motifs, we identified the stem cell factor SALL4 which contains multiple zinc fingers. Mutation of the domain responsible for AT binding drastically reduced SALL4 genome occupancy and prematurely up-regulated genes in proportion to their AT content. Inactivation of this single AT-binding zinc-finger cluster mimicked defects seen in <jats:italic>Sall4</jats:italic>-null cells, including precocious differentiation of embryonic stem cells and embryonic lethality in mice. In contrast, deletion of two other zinc-finger clusters was phenotypically neutral. Our data indicate that loss of pluripotency is triggered by down-regulation of SALL4, leading to de-repression of a set of AT-rich genes that promotes neuronal differentiation. We conclude that base composition is not merely a passive by-product of genome evolution, but constitutes a signal that aids control of cell fate.</jats:p>

Structural insights into AT-rich DNA recognition by SALL family proteins

“…Given that SALL4 ZFC1 binds to AT-rich DNAs weaker than SALL4 ZFC4 , it might be insufficient to maintain the occupancy of SALL4 after the deletion of ZFC4, consistent with previous report that mutation or deletion of SALL4 ZFC4 impairs the targeting of SALL4 at genome sites 14 .…”

“…Very recently, two lines of work independently identified Spalt-like transcription factor 4 (SALL4) as the AT-rich DNA binding protein via pull-down mass spectrometry screen and protein binding microarray, respectively 14,15 . SALL4 belongs to the Spaltlike transcription factors (SALLs) family, which includes SALL1-4 16 .…”

“…Although AT-rich regions are also highly enriched in some important regulatory genomic DNA elements, including TATA box 10, 11 , whether they also recruit sequence-specific TFs and how they function in embryo development are largely unknown 12, 13 . Very recently, two lines of work independently identified Spalt-like transcription factor 4 (SALL4) as the AT-rich DNA binding protein via pull-down mass spectrometry screen and protein binding microarray, respectively 14, 15 . SALL4 belongs to the Spalt-like transcription factors (SALLs) family, which includes SALL1-4 16 .…”

“…Dysfunctional SALL4 pathway is associated with severe human diseases, including Holt-Oram syndrome (HOS) 17 , acro-renal-ocular syndrome (AROS) 18 , leukemogenesis and other cancers 19 . SALL4 contains eight zinc fingers and they form four clusters 14 . The zinc finger cluster 4 (ZFC4) is essential for SALL4 to recognize AT-rich sequence to repress expression of a variety of genes, and its mutation results in abnormal differentiation and embryonic lethality 14, 15 .…”

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation inARID1B-related neurodevelopmental disorders

“…unexplored. It was recently demonstrated that this transcription factor has affinity for AT-rich regions 48 , thus providing further support to the ARID1B-SALL4 interaction. SALL4 mutations are also associated with developmental syndromes, including Okihiro syndrome, Holt-Oram syndrome, and Townes-Brocks Syndrome 49 .…”