Structural studies of SALL family protein zinc finger cluster domains in complex with DNA reveal preferential binding to an AATA tetranucleotide motif

Abstract

The Spalt-like 4 transcription factor (SALL4) plays an essential role in controlling the pluripotent property of embryonic stem cells via binding to AT-rich regions of genomic DNA, but structural details on this binding interaction have not been fully characterized. Here, we present crystal structures of the zinc finger cluster 4 (ZFC4) domain of SALL4 (SALL4ZFC4) bound with different dsDNAs containing a conserved AT-rich motif. In the structures, two zinc fingers of SALL4ZFC4 recognize an AATA tetranucleotide. We also solved the DNA-bound structures of SALL3ZFC4 and SALL4ZFC1. These structures illuminate a common preference for the AATA tetranucleotide shared by ZFC4 of SALL1, SALL3, and SALL4. Furthermore, our cell biology experiments demonstrate that the DNA-binding activity is essential for SALL4 function as DNA-binding defective mutants of mouse Sall4 failed to repress aberrant gene expression in Sall4-/- mESCs. Thus, these analyses provide new insights into the mechanisms of action underlying SALL family proteins in controlling cell fate via preferential targeting to AT-rich sites within genomic DNA during cell differentiation. The Spalt-like 4 transcription factor (SALL4) plays an essential role in controlling the pluripotent property of embryonic stem cells via binding to AT-rich regions of genomic DNA, but structural details on this binding interaction have not been fully characterized. Here, we present crystal structures of the zinc finger cluster 4 (ZFC4) domain of SALL4 (SALL4ZFC4) bound with different dsDNAs containing a conserved AT-rich motif. In the structures, two zinc fingers of SALL4ZFC4 recognize an AATA tetranucleotide. We also solved the DNA-bound structures of SALL3ZFC4 and SALL4ZFC1. These structures illuminate a common preference for the AATA tetranucleotide shared by ZFC4 of SALL1, SALL3, and SALL4. Furthermore, our cell biology experiments demonstrate that the DNA-binding activity is essential for SALL4 function as DNA-binding defective mutants of mouse Sall4 failed to repress aberrant gene expression in Sall4-/- mESCs. Thus, these analyses provide new insights into the mechanisms of action underlying SALL family proteins in controlling cell fate via preferential targeting to AT-rich sites within genomic DNA during cell differentiation. Transcription factors (TFs) play essential roles in embryo development through binding to the specific regions of genomic DNA to direct different complexes in mediating programmable gene transcription (1Spitz F. Furlong E.E. Transcription factors: from enhancer binding to developmental control.Nat. Rev. Genet. 2012; 13: 613-626Crossref PubMed Scopus (1259) Google Scholar, 2Lambert S.A. Jolma A. Campitelli L.F. Das P.K. Yin Y. 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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 (14Pantier R. Chhatbar K. Quante T. Skourti-Stathaki K. Cholewa-Waclaw J. Alston G. et al.SALL4 controls cell fate in response to DNA base composition.Mol. Cell. 2021; 81: 845-858.e848Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 15Kong N.R. Bassal M.A. Tan H.K. Kurland J.V. Yong K.J. Young J.J. et al.Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression.Cell Rep. 2021; 34108574Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). SALL4 belongs to the Spalt-like transcription factors (SALLs) family, which includes SALL1-4 (16Alvarez C. Quiroz A. Benitez-Riquelme D. Riffo E. Castro A.F. Pincheira R. SALL proteins; common and antagonistic roles in cancer.Cancers (Basel). 2021; 13: 6292Crossref PubMed Scopus (7) Google Scholar). Both SALL1 and SALL3 contain four zinc finger clusters (ZFCs), termed as ZFC1-4, whereas SALL2 and SALL4 contain three ZFCs and lack ZFC4 and ZFC3, respectively (14Pantier R. Chhatbar K. Quante T. Skourti-Stathaki K. Cholewa-Waclaw J. Alston G. et al.SALL4 controls cell fate in response to DNA base composition.Mol. Cell. 2021; 81: 845-858.e848Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). SALL4 is highly expressed in embryonic stem cells (ESCs) and several tumors but absent in most adult tissues. Dysfunctional SALL4 pathway is associated with severe human diseases, including Holt-Oram syndrome (17Kohlhase J. Schubert L. Liebers M. Rauch A. Becker K. Mohammed S.N. et al.Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy.J. Med. Genet. 2003; 40: 473-478Crossref PubMed Scopus (142) Google Scholar), acro-renal-ocular syndrome (18Kohlhase J. Chitayat D. Kotzot D. Ceylaner S. Froster U.G. Fuchs S. et al.SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders.Hum. Mutat. 2005; 26: 176-183Crossref PubMed Scopus (86) Google Scholar), leukemogenesis, and other cancers (19Yang L. Liu L. Gao H. Pinnamaneni J.P. Sanagasetti D. Singh V.P. et al.The stem cell factor SALL4 is an essential transcriptional regulator in mixed lineage leukemia-rearranged leukemogenesis.J. Hematol. Oncol. 2017; 10: 159Crossref PubMed Scopus (25) Google Scholar). SALL4 contains seven zinc fingers within its three clusters and an additional single zinc finger near the N-terminus (14Pantier R. Chhatbar K. Quante T. Skourti-Stathaki K. Cholewa-Waclaw J. Alston G. et al.SALL4 controls cell fate in response to DNA base composition.Mol. Cell. 2021; 81: 845-858.e848Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). The 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 (14Pantier R. Chhatbar K. Quante T. Skourti-Stathaki K. Cholewa-Waclaw J. Alston G. et al.SALL4 controls cell fate in response to DNA base composition.Mol. Cell. 2021; 81: 845-858.e848Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 15Kong N.R. Bassal M.A. Tan H.K. Kurland J.V. Yong K.J. Young J.J. et al.Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression.Cell Rep. 2021; 34108574Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). All SALL proteins except SALL2 recognize AT-rich DNAs via ZFC4 (14Pantier R. Chhatbar K. Quante T. Skourti-Stathaki K. Cholewa-Waclaw J. Alston G. et al.SALL4 controls cell fate in response to DNA base composition.Mol. Cell. 2021; 81: 845-858.e848Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 15Kong N.R. Bassal M.A. Tan H.K. Kurland J.V. Yong K.J. Young J.J. et al.Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression.Cell Rep. 2021; 34108574Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Despite the critical role of SALL4ZFC4 in embryo development and its conservation in other SALL proteins, how it binds to AT-rich DNAs and how the SALL4 occupancy at AT-rich regions influences gene expression remain elusive. By using isothermal titration calorimetry (ITC)-binding assays, we ascertain that the ZFC4 of SALL3 and SALL4 prefer AT-rich DNAs. By solving the structures of SALL3 and SALL4 ZFC4 bound with different AT-rich DNAs, we revealed that the SALL3 and SALL4 ZFC4 recognize AT-rich DNAs through the Gln-Ade residue base pairing and thymine-mediated van der Waals interactions. In addition, we found that SALL4ZFC1 also serves as a binder of AT-rich DNAs, albeit with weaker binding affinity. Inspired by previous finding that loss of Sall4 in ESCs causes aberrant neural gene expression (20Miller A. Ralser M. Kloet S.L. Loos R. Nishinakamura R. Bertone P. et al.Sall4 controls differentiation of pluripotent cells independently of the Nucleosome Remodelling and Deacetylation (NuRD) complex.Development. 2016; 143: 3074-3084Crossref PubMed Scopus (43) Google Scholar), we evaluated the functional relevance of DNA-binding and found that DNA-binding deficient SALL4 to repress aberrant expression of several genes, as and our not how ZFC4 of SALL proteins AT-rich DNAs but also on the of binding to AT-rich DNA in the binding activity of SALL4 to DNAs with different base we a of human SALL4 SALL4ZFC4 and its binding different dsDNAs by using with previous (14Pantier R. Chhatbar K. Quante T. Skourti-Stathaki K. Cholewa-Waclaw J. Alston G. et al.SALL4 controls cell fate in response to DNA base composition.Mol. Cell. 2021; 81: 845-858.e848Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 15Kong N.R. Bassal M.A. Tan H.K. Kurland J.V. Yong K.J. Young J.J. et al.Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression.Cell Rep. 2021; 34108574Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar), SALL4ZFC4 binds to different DNAs, containing with in a range of to and and In the binding four by whether other SALL family DNA-binding we and the ZFC4 domain of SALL3 to and its DNA-binding property by binding analyses that SALL3ZFC4 binds to the DNA with a of to that of SALL4ZFC4 SALL3ZFC4 binding DNAs Thus, we that ZFC4 of SALL3 and SALL4 recognize AT-rich DNAs by an in binding into the underlying AT-rich DNA recognition by we solved the crystal structure of the SALL4ZFC4 with a in a The of protein and the are of and are two in an with of bound with two SALL4ZFC4 SALL4ZFC4 is of two zinc termed as and and In SALL4ZFC4 binds to the of the with zinc fingers whereas the other binds to the of the with that binding that SALL4ZFC4 binds to the in a of binding of the SALL4ZFC4 to the is to the crystal and the to its our structural on the SALL4ZFC4 bound at the of the binding to the of DNA SALL4ZFC4 the DNA and with it via the and and belongs to finger motif that a Although the are conserved in the the two is in SALL2 that of SALL2 DNA-binding In the the tetranucleotide is recognized by SALL4ZFC4 via and van der Waals The and of SALL4 are to the and of The of also two with of and respectively The residue base pairing is to the in the DNA-bound CXXC domain structures C. Bian C. Lam R. Dong A. Min J. The structural basis for selective binding of non-methylated CpG islands by the CFP1 CXXC domain.Nat. Commun. 2011; 2: 227Crossref PubMed Scopus (100) Google Scholar, Y. C. A. Bian C. et CXXC domain and activity regulate genes for and neural 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). The of and van der Waals with the of which with the and Furthermore, of SALL4ZFC4 van der Waals interaction with of to in the and and van der Waals SALL4ZFC4 the to recognize the AATA motif within the In to the the is by DNA and the of SALL4. The and with and the of and with and the and two with and the of and are to the of and and and several with the and we to the roles of SALL4 the the DNA binding by In binds to the DNA with to the the critical role of and The mutation the DNA binding by the of the van der Waals and the the DNA the essential role of and DNA and experiments the at the that and are in most of we to to how it on its DNA All on the binding that and the binding to AT-rich DNA whereas and the by to SALL4 and but not we the structures of SALL4 bound with and respectively is by a the the of and of is which results in the of the and the and and In addition, the and In the structure of SALL4 bound with and of and of are which the and In not the and and also the is to the as Thus, our structural and binding that SALL4 an a within the The recognition is by the and the as well as the interactions. whether the AATA recognition by SALL4ZFC4 also for dsDNAs of different we determined the structure of SALL4ZFC4 with a containing two In the the two SALL4ZFC4 recognize and within the to the in a The sequence-specific recognition is the as in the DNA the also that SALL4ZFC4 binds to the with two in a range of to binds to the DNA with to of the binding the Thus, we that SALL4ZFC4 AATA other within AT-rich within the of whether DNA recognition also for other SALL we determined the crystal structure of SALL3ZFC4 with the AT-rich in a is in an to that of SALL4 ZFC4 with SALL3ZFC4 binds to the of the DNA via its The DNA-bound SALL3ZFC4 structure is well with the two SALL4 complexes with the in a range of to the conserved of SALL and van der Waals found SALL3ZFC4 and SALL3 the of SALL4 two with and of SALL3, the of SALL4 and van der Waals interaction with which a with additional van der Waals interaction with recognition by SALL3ZFC4 is the as that by In addition, the DNA and SALL3 including and are also conserved in the SALL4 that the binding of SALL3 are conserved in SALL1 but not in we that the preference for dsDNAs is conserved in ZFC4 of SALL1, SALL3, and SALL4. of SALL4 and ZFC4 that SALL4ZFC4 in the recognition of AATA motif are conserved in SALL4ZFC1 except which is by an in SALL4ZFC1 We the DNA binding of SALL4ZFC1 by that SALL4ZFC1 binds to the AT-rich DNA with a of and binds to the AT-rich DNA with in a range of to weaker that for We solved the structure of SALL4ZFC1 with the AT-rich DNA at are three dsDNAs and SALL4ZFC1 in with bound with two SALL4ZFC1 In the SALL4ZFC1 base via of and in the of and whereas of and with in the of and The of and are in a range of to and the weaker in the of we the structure of DNA-bound structure of SALL4ZFC1 with that of SALL4ZFC4 and found that of ZFC4 is to the of to the the DNA and the of In SALL4ZFC1 the of SALL4ZFC4 to with the DNA which the and SALL4ZFC1 the of SALL4ZFC4 with the structural we found that of SALL4ZFC4 the DNA-binding by our structural by and binding that SALL4ZFC1 also AT-rich DNA, albeit with weaker affinity. In mouse binding of SALL4 to AT-rich enhancer expression of differentiation genes (14Pantier R. Chhatbar K. Quante T. Skourti-Stathaki K. Cholewa-Waclaw J. Alston G. et al.SALL4 controls cell fate in response to DNA base composition.Mol. Cell. 2021; 81: 845-858.e848Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). whether loss of DNA binding in the SALL4ZFC4 mutation has a we mouse ESCs from ESCs by which not into the we ESCs with mouse Sall4 mouse Sall4 SALL4 to mouse SALL4 we Sall4 expression by of Sall4 and Sall4 is and to Sall4 expression in ESCs we expression of several neural differentiation genes to which SALL4 is We also SALL4 experiments in to SALL4 motif of AT-rich which is with a SALL4 result in mouse ESCs (14Pantier R. Chhatbar K. Quante T. Skourti-Stathaki K. Cholewa-Waclaw J. Alston G. et al.SALL4 controls cell fate in response to DNA base composition.Mol. Cell. 2021; 81: 845-858.e848Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). experiments also of SALL4 near the gene previously (20Miller A. Ralser M. Kloet S.L. Loos R. Nishinakamura R. Bertone P. et al.Sall4 controls differentiation of pluripotent cells independently of the Nucleosome Remodelling and Deacetylation (NuRD) complex.Development. 2016; 143: 3074-3084Crossref PubMed Scopus (43) Google Scholar), expression is in Sall4-/- to the Both Sall4 and Sall4 into Sall4-/- aberrant expression of SALL4 also enriched in the region and are on chromosome of in Sall4-/- The Sall4 aberrant expression of but Sall4 failed to repress expression not Sall4 aberrant expression of and a for We found that near the gene and of at the region contain the AATA which found in of the of the of aberrant expression of and genes is with the that DNA binding of SALL4 to the of these gene In addition, of by Sall4 associated with the binding of SALL4 to the AT-rich region via its domain, with our structural and fingers proteins in human to the and of as TFs B. C. J. et and of the human PubMed Scopus Google Scholar, M. A. F. C. M. M. et proteins in and 2017; PubMed Scopus Google Scholar). the motif of zinc finger TFs is important for roles in gene SALL family are a of zinc finger proteins important roles in cell development and differentiation. Dysfunctional SALL proteins are associated with different of In this we the conserved DNA recognition by SALL family through several structures of SALL proteins with DNA SALL proteins a conserved as of SALL4 of SALL3, to recognize the of base of SALL proteins with the of the In addition, the an at the these SALL proteins the to AT-rich DNAs. that SALL4ZFC1 binds to AT-rich DNAs weaker it to the occupancy of SALL4 the of with previous that mutation of SALL4ZFC4 the targeting of SALL4 at sites (14Pantier R. Chhatbar K. Quante T. Skourti-Stathaki K. Cholewa-Waclaw J. Alston G. et al.SALL4 controls cell fate in response to DNA base composition.Mol. Cell. 2021; 81: 845-858.e848Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). It has been reported that transcriptional AT-rich DNAs A. D. of AT-rich DNA binding sites by the Full Text Full Text PDF PubMed Scopus Google Scholar), which to it with the SALL4ZFC4 The DNA recognition in two complexes are different the AT-rich motif but in a from that SALL4 and DNA binds to as a with the tetranucleotide of into the of tetranucleotide by two with the base The other are by B. of with and with and and with and A. D. of AT-rich DNA binding sites by the Full Text Full Text PDF PubMed Scopus Google Scholar). The AT-rich recognition by is from the binding in the SALL4 which is by the mutations in SALL4 known to result in Okihiro single mutations within including is reported to associated with Okihiro on the of in identified single mutations in SALL4ZFC1 and SALL4ZFC4 have on protein DNA binding including and of SALL4ZFC1 and and of SALL4ZFC4 an the and the of SALL4ZFC1 the interaction with DNA and the binding of SALL4ZFC4 with DNA whereas and not the binding to but also the with DNA our that and the by and DNA-binding and These mutations that DNA-binding of SALL4ZFC4 mutants are associated with human It has been reported that the of SALL4 with the remodeling that chromatin structure in ESCs C. J.P. et for SALL4 by its with a Natl. Acad. Sci. U. S. A. 2018; PubMed Scopus Google Scholar, of and factor binding revealed by of the Rep. 13: Full Text Full Text PDF PubMed Scopus Google Scholar). our structural roles of SALL4 in sequence recognition by and remodeling In this our not the conserved DNA recognition by SALL family but also insights into a how SALL4 mutations result in human cancers via the expression of regulators as In our not into the AT-rich DNA recognition by SALL4ZFC4 and but also that the binding of SALL4 at specific AT-rich genomic DNA regions influences cell differentiation and cell fate in The sequence SALL4ZFC4 by from a human SALL4ZFC1 and SALL3ZFC4 by the sequence human which and by All of into and the into in at the The protein at for by and by at 4 for and in a containing 20 and at 4 for and SALL4ZFC4 by and by 20 and of the protein by and with the containing 20 and SALL4ZFC4 by and The protein to in the containing 20 and and at and of SALL4ZFC1 and SALL3ZFC4 in the as for mutations by using two and containing for mutants are in All mutants in the as for experiments on a at by of protein into cell containing DNA, with a of and a of The binding in a containing 20 and experiments by proteins into the which during and by The determined from a of two experiments of dsDNAs for are in The SALL4ZFC4 is in 20 its experiments by of into cell containing are in All using the at protein is mixed with at a of of SALL4ZFC4 in with the by of with of well containing and of SALL4ZFC4 in with the by of with of well containing and of in with the by of with of well containing and of SALL4ZFC1 in with the by of with of well containing and in in a of The on and at and with of in PubMed Scopus Google Scholar, M. M. The of and structure to an in Biol. PubMed Scopus Google Biol. 2010; PubMed Scopus Google Scholar). Although the of SALL4ZFC4 with DNA at zinc to the The structure of SALL4ZFC4 solved by P. J.P. in the for Biol. 2011; PubMed Scopus Google Scholar), with the DNA by P. K. for Biol. PubMed Scopus Google Scholar), and the by R.W. T.R. et new for structure Biol. 58: PubMed Scopus Google Scholar). The other complexes solved by using R.W. R.J. 40: PubMed Scopus Google with previously solved SALL4ZFC4 as the the and by and by R.W. T.R. et new for structure Biol. 58: PubMed Scopus Google Scholar). The details and structure in mouse ESCs previously M. C. A. S. Y. M. et al.The of a gene in Okihiro syndrome, is essential for embryonic stem cell and with in and PubMed Scopus Google Scholar). are in the C. T. F. J. A. for and of mouse embryonic stem PubMed Scopus Google Scholar). Sall4-/- ESCs by and with B. Y. S. M. protein via Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). and the Sall4-/- by genomic as previously M. C. A. S. Y. M. et al.The of a gene in Okihiro syndrome, is essential for embryonic stem cell and with in and PubMed Scopus Google Scholar). mouse Sall4 in the A. L. M. et fingers are structures Biol. 2016; PubMed Scopus Google Scholar). The Sall4 by using DNA and the to a S. M. H. et factor domain mutations in present for and Cell. 2018; Full Text Full Text PDF PubMed Scopus Google and using with Sall4 and by cells and for RNA using the RNA and DNA using to the using and in P.J. S. for of DNA binding 2017; PubMed Scopus Google as in the using mouse ESCs cells in the (20Miller A. Ralser M. Kloet S.L. Loos R. Nishinakamura R. Bertone P. et al.Sall4 controls differentiation of pluripotent cells independently of the Nucleosome Remodelling and Deacetylation (NuRD) complex.Development. 2016; 143: 3074-3084Crossref PubMed Scopus (43) Google Scholar). at a from to to and using containing DNA and with DNA using the and during using using a on a using and and with with using the mouse as identified using using the from using to present in The of sequence the of for motif with using and the regions from for the The and structure factors for the structures of SALL4ZFC4 with SALL4ZFC4 with SALL3ZFC4 with and SALL4ZFC1 with into and in the with the contains The that they have of with the of this We the from the of for in at for during We also and Nishinakamura for mouse R. and C. T. and C. T. M. D. S. M. H. D. J. Y. and C. Y. and C. T. M. D. S. M. H. D. J. Y. and C. and Y. K. and C. C. is by the of and for the the of the of the for and and Young Y. is by a from of of and of and of the of

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