MEF2-dependent Recruitment of the HAND1 Transcription Factor Results in Synergistic Activation of Target Promoters

HAND proteins are tissue-restricted members of the basic helix-loop-helix transcription factor family that play critical roles in cell differentiation and organogenesis including placental, cardiovascular, and craniofacial development. Nevertheless, the molecular basis underlying the developmental action of HAND proteins remains undefined. Within the embryo, HAND1 is first detected in the developing heart where it becomes restricted to the atrial and left ventricular compartments, a pattern identical to that of the Nppa gene, which encodes atrial natriuretic factor, the major secretory product of the heart. We hereby report that the cardiac atrial natriuretic factor promoter is directly activated by HAND1, making it the first known HAND1 transcriptional target. The action of HAND1 does not require heterodimerization with class I basic helix-loop-helix factors or DNA binding through E-box elements. Instead, HAND1 is recruited to the promoter via physical interaction with MEF2 proteins. MEF2/HAND1 interaction results in synergistic activation of MEF2-dependent promoters, and MEF2 binding sites are sufficient to mediate this synergy. MEF2 binding to DNA is not enhanced in the presence of HAND1. Instead, cooperativity likely results from corecruitment of co-activators such as CREB-binding protein. The related HAND2 protein can with HAND proteins as developmental co-activators of the MEF2 family of transcription a HAND action in the heart and a to the of HAND action in HAND proteins are tissue-restricted members of the basic helix-loop-helix transcription factor family that play critical roles in cell differentiation and organogenesis including placental, cardiovascular, and craniofacial development. Nevertheless, the molecular basis underlying the developmental action of HAND proteins remains undefined. Within the embryo, HAND1 is first detected in the developing heart where it becomes restricted to the atrial and left ventricular compartments, a pattern identical to that of the Nppa gene, which encodes atrial natriuretic factor, the major secretory product of the heart. We hereby report that the cardiac atrial natriuretic factor promoter is directly activated by HAND1, making it the first known HAND1 transcriptional target. The action of HAND1 does not require heterodimerization with class I basic helix-loop-helix factors or DNA binding through E-box elements. Instead, HAND1 is recruited to the promoter via physical interaction with MEF2 proteins. MEF2/HAND1 interaction results in synergistic activation of MEF2-dependent promoters, and MEF2 binding sites are sufficient to mediate this synergy. MEF2 binding to DNA is not enhanced in the presence of HAND1. Instead, cooperativity likely results from corecruitment of co-activators such as CREB-binding protein. The related HAND2 protein can with HAND proteins as developmental co-activators of the MEF2 family of transcription a HAND action in the heart and a to the of HAND action in The HAND1 and HAND2 proteins of the tissue-restricted basic atrial natriuretic CREB-binding basic atrial natriuretic CREB-binding factors that are in and in the heart and the HAND are the heart pattern becomes as the heart with HAND1 the and left HAND2 the that proteins are cardiac cell differentiation and heart of to of that ventricular and the of HAND1, of in heart by of and where HAND1 is Nevertheless, that not to the left a cell HAND1 in this cardiac in that of HAND1 in the of including the atrial natriuretic factor and this that HAND1 is not a of the left ventricular that it with transcription factors to of in the heart and that of HAND1 in cardiac to cardiac with in differentiation and to roles HAND proteins in craniofacial and development. the molecular underlying the of HAND proteins in organogenesis by of to with the class I the not binding of to DNA E-box the of to in the of HAND1 the of HAND1 to as a transcription from sites by such the transcription factor, which to with the of HAND1 and transcription the of HAND1 to with can the of of the the of which and in the that HAND1 as a by class I factors in a of that of the proteins HAND1 to transcriptional of transcription the as to and HAND1 as a transcriptional is not of HAND1 action transcriptional the of the related HAND2 factor, of action of is and DNA binding as a with class proteins The does not HAND2 binding to HAND2 is recruited to the promoter through interaction with interaction with proteins a of class factors as and in HAND2 to with the protein in with activation of the promoter this the of HAND2 to the promoter enhanced by the of interaction and of the which the binding to in the ventricular to that a transcriptional HAND1. the restricted pattern of HAND1 in heart and left is of that of the Nppa gene, which encodes the major secretory product of the heart. with in the left in is the of HAND1 in the sufficient to transcription of the We the cardiac promoter a transcriptional HAND1. results that HAND1 is a transcriptional of and the first a transcriptional HAND1. The a HAND which physical and interaction with MEF2 proteins. the molecular underlying HAND in cardiac and and from and a of in as and in with as the results are the of to in with DNA and of the promoter as as MEF2 and or The in and The HAND1 The a of and as with of with and in of to of a of and The and the in of and by of in with and to the The in of and the proteins and MEF2 proteins in the in transcription binding as with of MEF2 and proteins with of HAND1 proteins in of with and The of proteins in binding by to by in of The protein in and by proteins and a and a and of and of the proteins as of of in of binding and and to by to a and as from with the The the and sites a of a HAND1, a by the that promoter are sufficient to of the in the heart. in HAND1 activated transcription from the promoter in in a in and in the class I factors and activated the promoter and and not proteins including and not in transcriptional activation of the promoter and not and in a of the promoter in the related HAND2 protein not the a with results that the promoter is to HAND1 and a to the of action of HAND1. a to the of HAND1 transcriptional the of HAND1 not a with transcriptional of the a activated the it to the action of HAND1 the promoter interaction with class I proteins or heterodimerization with and a in to the promoter that HAND1 activation of interaction with transcription factors likely not class I and DNA the of HAND1 of the promoter to the HAND1 and of and HAND1 activation by the activation that and a which is in from that the E-box is a binding as in binding and results that HAND1 and class I the promoter via to the HAND1 that and a of this HAND1 activation the that HAND1 action with MEF2 proteins. We HAND1 MEF2 binding to the or not or with HAND1, not in MEF2 binding in the presence of HAND1 HAND1 not to the or to E-box not that transcriptional activation of the promoter by HAND1 does not binding of HAND1 to We HAND1 activation to interaction with factors is in the related HAND2 protein to with of the sites in the of the promoter not HAND1 activation of including the or the HAND1 activation and not results that HAND1 is recruited to the promoter via interaction with or MEF2 HAND1 and elements. The with and of the promoter in and or The of the binding sites are in the and are of the The as in of and of The are the of in with DNA the to HAND1 and to elements. are in the and MEF2 that the E-box is a binding from or with and to of or the E-box a in the E-box The to a E-box that binding the from with or with in the presence or not of HAND1. DNA are and E-box from the The of the MEF2 is are in a MEF2 directly HAND1 and MEF2 by the with or HAND1 or in that in the presence of HAND1 and in synergistic transcriptional with of the related HAND2 protein in transcriptional cooperativity with MEF2 The DNA binding of MEF2 sufficient to to a that MEF2 proteins to HAND1 to with a promoter by a that that MEF2 proteins recruited to via proteins with a the promoter that binding sites is to HAND1 or MEF2 the of in this promoter to MEF2/HAND1 in presence of the transcription factors the presence of the binding and promoter activation it that MEF2 can HAND1 to through a or with a in DNA binding the to with proteins and HAND1 as as in with HAND1 the promoter in in where the this not not activation of by MEF2 and HAND1. and where in the DNA binding of The and are and in the The which interaction with are as the of promoter in the presence or of HAND1 is the of HAND1 the are from of to in with and in of and HAND1 in in and in and a of the and of synergy. in as interaction HAND1 and the and the in as The are the of results that HAND1 action a We proteins and HAND1 in physical interaction the proteins. this interaction in and in MEF2 proteins. as to of the MEF2 proteins and as as the not the that HAND1 and MEF2 MEF2 proteins in DNA binding and the to HAND1 that are DNA binding and HAND1 as from the that not MEF2 binding to DNA cooperativity the factors corecruitment of such transcriptional as in of in of MEF2 as as activation of the cooperativity not restricted to the The promoter that is in and activated by HAND1 and the are with a HAND proteins as co-activators of the MEF2 family of transcription the of HAND proteins heart the molecular by which HAND proteins transcription of and are not this that the promoter is a HAND1. is by that of HAND1 in the is sufficient to the and that are in with to a HAND1. We that HAND proteins with MEF2 factors to cardiac The is by physical and MEF2 to HAND proteins to DNA through binding to or via a a HAND action in the heart and that proteins can transcription via and through interaction with by proteins to with and with class factor, and transcription through a MEF2 binding or E-box The that MEF2 with the HAND that interaction with MEF2 proteins a of class MEF2 proteins are with class factors in cell such as which MEF2 and and where MEF2 is with such as and to HAND in to the MEF2 and HAND1 as are in and the roles of MEF2 the differentiation of or to interaction with MEF2 a the action of tissue-restricted class MEF2 interaction with or with interaction does not to require class I is by the MEF2/HAND1 synergistic activation of the in which class I of of the in to MEF2/HAND1 activation not the DNA binding of MEF2 sufficient with HAND1 that HAND1 is to transcriptional the MEF2 or activation sufficient HAND1 recruited to DNA by MEF2 and in co-activators or it MEF2 such this it is that the of HAND2 to with the the of MEF2 is known to directly this and it is that HAND1 binding to a MEF2 HAND and HAND1 can to and a The promoter and a a in HAND1 transcriptional does not to in HAND1 results not a or class I in HAND1 transcriptional the and that the of HAND2 that transcriptional activation by HAND proteins interaction with HAND2 a the the by which this that the HAND2 by The to and HAND2 and that HAND2 as a of the protein not the of that HAND1 with it not the promoter or in with results and of that HAND1 is of not cooperativity and HAND1, the MEF2/HAND1 the promoter by the of that MEF2 a interaction not that HAND1 transcription of and that of such as through with transcription and that HAND1 activation of in and the MEF2 or not require the HAND1 or in with MEF2 activation of the promoter in the of that HAND1 can with and MEF2 and transcription via interaction The HAND1 developmental or of the the MEF2 binding to promoter in and as by in this which promoter by in in and MEF2 is and that HAND1 is it is to that HAND1 a MEF2 that to of MEF2 the that HAND1 is a transcriptional and a MEF2 the of MEF2 proteins in and the of including HAND1, are the of the and as HAND1 of the HAND1 in organogenesis and The HAND1 and HAND2 proteins of the tissue-restricted basic atrial natriuretic CREB-binding basic atrial natriuretic CREB-binding factors that are in and in the heart and the HAND are the heart pattern becomes as the heart with HAND1 the and left HAND2 the that proteins are cardiac cell differentiation and heart of to of that ventricular and the of HAND1, of in heart by of and where HAND1 is Nevertheless, that not to the left a cell HAND1 in this cardiac in that of HAND1 in the of including the atrial natriuretic factor and this that HAND1 is not a of the left ventricular that it with transcription factors to of in the heart and that of HAND1 in cardiac to cardiac with in differentiation and to roles HAND proteins in craniofacial and development. the molecular underlying the of HAND proteins in organogenesis undefined. HAND1 by of to with the class I the not binding of to DNA E-box the of to in the of HAND1 the of HAND1 to as a transcription from sites by such the transcription factor, which to with the of HAND1 and transcription the of HAND1 to with can the of of the the of which and in the that HAND1 as a by class I factors in a of that of the proteins HAND1 to transcriptional of transcription the as to and HAND1 as a transcriptional is not of HAND1 action transcriptional the of the related HAND2 factor, of action of is and DNA binding as a with class proteins The does not HAND2 binding to HAND2 is recruited to the promoter through interaction with interaction with proteins a of class factors as and in HAND2 to with the protein in with activation of the promoter this the of HAND2 to the promoter enhanced by the of interaction and of the which the binding to in the ventricular to that a transcriptional HAND1. the restricted pattern of HAND1 in heart and left is of that of the Nppa gene, which encodes the major secretory product of the heart. with in the left in is the of HAND1 in the sufficient to transcription of the We the cardiac promoter a transcriptional HAND1. results that HAND1 is a transcriptional of and the first a transcriptional HAND1. The a HAND which physical and interaction with MEF2 proteins. the molecular underlying HAND in cardiac and and from and a of in as and in with as the results are the of to in with DNA and of the promoter as as MEF2 and or The in and The HAND1 The a of and as with of with and in of to of a of and The and the in of and by of in with and to the The in of and the proteins and MEF2 proteins in the in transcription binding as with of MEF2 and proteins with of HAND1 proteins in of with and The of proteins in binding by to by in of The protein in and by proteins and a and a and of and of the proteins as of of in of binding and and to by to a and as from with the The the and sites and from and a of in as and in with as the results are the of to in with DNA and of the promoter as as MEF2 and or The in and The HAND1 The a of and as with of with and in of to of a of and The and the in of and by of in with and to the The in of and the proteins and MEF2 proteins in the in transcription binding as with of MEF2 and proteins with of HAND1 proteins in of with and The of proteins in binding by to by in of The protein in and by proteins and a and a and of and of the proteins as of of in of binding and and to by to a and as from with the The the and sites a of a HAND1, a by the that promoter are sufficient to of the in the heart. in HAND1 activated transcription from the promoter in in a in and in the class I factors and activated the promoter and and not proteins including and not in transcriptional activation of the promoter and not and in a of the promoter in the related HAND2 protein not the a with results that the promoter is to HAND1 and a to the of action of HAND1. a to the of HAND1 transcriptional the of HAND1 not a with transcriptional of the a activated the it to the action of HAND1 the promoter interaction with class I proteins or heterodimerization with and a in to the promoter that HAND1 activation of interaction with transcription factors likely not class I and DNA the of HAND1 of the promoter to the HAND1 and of and HAND1 activation by the activation that and a which is in from that the E-box is a binding as in binding and results that HAND1 and class I the promoter via to the HAND1 that and a of this HAND1 activation the that HAND1 action with MEF2 proteins. We HAND1 MEF2 binding to the or not or with HAND1, not in MEF2 binding in the presence of HAND1 HAND1 not to the or to E-box not that transcriptional activation of the promoter by HAND1 does not binding of HAND1 to We HAND1 activation to interaction with factors is in the related HAND2 protein to with of the sites in the of the promoter not HAND1 activation of including the or the HAND1 activation and not results that HAND1 is recruited to the promoter via interaction with or MEF2 a MEF2 directly HAND1 and MEF2 by the with or HAND1 or in that in the presence of HAND1 and in synergistic transcriptional with of the related HAND2 protein in transcriptional cooperativity with MEF2 The DNA binding of MEF2 sufficient to to a that MEF2 proteins to HAND1 to with a promoter by a that that MEF2 proteins recruited to via proteins with a the promoter that binding sites is to HAND1 or MEF2 the of in this promoter to MEF2/HAND1 in presence of the transcription factors the presence of the binding and promoter activation it that MEF2 can HAND1 to through a or with a in DNA binding the to with proteins and HAND1 as as in with HAND1 the promoter in in where the this not not activation of by MEF2 and HAND1. and where in the DNA binding of The and are and in the The which interaction with are as the of promoter in the presence or of HAND1 is the of HAND1 the are from of to in with and in of and HAND1 in in and in and a of the and of synergy. in as interaction HAND1 and the and the in as The are the of results that HAND1 action a We proteins and HAND1 in physical interaction the proteins. this interaction in and in MEF2 proteins. as to of the MEF2 proteins and as as the not the that HAND1 and MEF2 MEF2 proteins in DNA binding and the to HAND1 that are DNA binding and HAND1 as from the that not MEF2 binding to DNA cooperativity the factors corecruitment of such transcriptional as in of in of MEF2 as as activation of the cooperativity not restricted to the The promoter that is in and activated by HAND1 and the are with a HAND proteins as co-activators of the MEF2 family of transcription HAND1 a of a HAND1, a by the that promoter are sufficient to of the in the heart. in HAND1 activated transcription from the promoter in in a in and in the class I factors and activated the promoter and and not proteins including and not in transcriptional activation of the promoter and not and in a of the promoter in the related HAND2 protein not the a with results that the promoter is to HAND1 and a to the of action of HAND1. a to the of HAND1 transcriptional the of HAND1 not a with transcriptional of the a activated the it to the action of HAND1 the promoter interaction with class I proteins or heterodimerization with and a in to the promoter that HAND1 activation of interaction with transcription factors likely not class I HAND1 and DNA the of HAND1 of the promoter to the HAND1 and of and HAND1 activation by the activation that and a which is in from that the E-box is a binding as in binding and results that HAND1 and class I the promoter via to the HAND1 that and a of this HAND1 activation the that HAND1 action with MEF2 proteins. We HAND1 MEF2 binding to the or not or with HAND1, not in MEF2 binding in the presence of HAND1 HAND1 not to the or to E-box not that transcriptional activation of the promoter by HAND1 does not binding of HAND1 to We HAND1 activation to interaction with factors is in the related HAND2 protein to with of the sites in the of the promoter not HAND1 activation of including the or the HAND1 activation and not results that HAND1 is recruited to the promoter via interaction with or MEF2 proteins. HAND1 a MEF2 directly HAND1 and MEF2 by the with or HAND1 or in that in the presence of HAND1 and in synergistic transcriptional with of the related HAND2 protein in transcriptional cooperativity with MEF2 The DNA binding of MEF2 sufficient to to a that MEF2 proteins to HAND1 to with a promoter by a that that MEF2 proteins recruited to via proteins with a the promoter that binding sites is to HAND1 or MEF2 the of in this promoter to MEF2/HAND1 in presence of the transcription factors the presence of the binding and promoter activation it that MEF2 can HAND1 to through a or with a in DNA binding the to with proteins and HAND1 as as in with HAND1 the promoter in in where the this not not The results that HAND1 action a We proteins and HAND1 in physical interaction the proteins. this interaction in and in MEF2 proteins. as to of the MEF2 proteins and as as the not the that HAND1 and MEF2 MEF2 proteins in DNA binding and the to HAND1 that are DNA binding and HAND1 as from the that not MEF2 binding to DNA cooperativity the factors corecruitment of such transcriptional as in of in of MEF2 as as activation of the cooperativity not restricted to the The promoter that is in and activated by HAND1 and the are with a HAND proteins as co-activators of the MEF2 family of transcription the of HAND proteins heart the molecular by which HAND proteins transcription of and are not this that the promoter is a HAND1. is by that of HAND1 in the is sufficient to the and that are in with to a HAND1. We that HAND proteins with MEF2 factors to cardiac The is by physical and MEF2 to HAND proteins to DNA through binding to or via a a HAND action in the heart and that proteins can transcription via and through interaction with by proteins to with and with class factor, and transcription through a MEF2 binding or E-box The that MEF2 with the HAND that interaction with MEF2 proteins a of class MEF2 proteins are with class factors in cell such as which MEF2 and and where MEF2 is with such as and to HAND in to the MEF2 and HAND1 as are in and the roles of MEF2 the differentiation of or to interaction with MEF2 a the action of tissue-restricted class MEF2 interaction with or with interaction does not to require class I is by the MEF2/HAND1 synergistic activation of the in which class I of of the in to MEF2/HAND1 activation not the DNA binding of MEF2 sufficient with HAND1 that HAND1 is to transcriptional the MEF2 or activation sufficient HAND1 recruited to DNA by MEF2 and in co-activators or it MEF2 such this it is that the of HAND2 to with the the of MEF2 is known to directly this and it is that HAND1 binding to a MEF2 HAND and HAND1 can to and a The promoter and a a in HAND1 transcriptional does not to in HAND1 results not a or class I in HAND1 transcriptional the and that the of HAND2 that transcriptional activation by HAND proteins interaction with HAND2 a the the by which this that the HAND2 by The to and HAND2 and that HAND2 as a of the protein not the of that HAND1 with it not the promoter or in with results and of that HAND1 is of not cooperativity and HAND1, the MEF2/HAND1 the promoter by the of that MEF2 a interaction not that HAND1 transcription of and that of such as through with transcription and that HAND1 activation of in and the MEF2 or not require the HAND1 or in with MEF2 activation of the promoter in the of that HAND1 can with and MEF2 and transcription via interaction The HAND1 developmental or of the the MEF2 binding to promoter in and as by in this which promoter by in in and MEF2 is and that HAND1 is it is to that HAND1 a MEF2 that to of MEF2 the that HAND1 is a transcriptional and a MEF2 the of MEF2 proteins in and the of including HAND1, are the of the and as HAND1 of the HAND1 in organogenesis and the of HAND proteins heart the molecular by which HAND proteins transcription of and are not this that the promoter is a HAND1. is by that of HAND1 in the is sufficient to the and that are in with to a HAND1. We that HAND proteins with MEF2 factors to cardiac The is by physical and MEF2 to HAND proteins to DNA through binding to or via a a HAND action in the heart and that proteins can transcription via and through interaction with MEF2-dependent by proteins to with and with class factor, and transcription through a MEF2 binding or E-box The that MEF2 with the HAND that interaction with MEF2 proteins a of class MEF2 proteins are with class factors in cell such as which MEF2 and and where MEF2 is with such as and to HAND in to the MEF2 and HAND1 as are in and the roles of MEF2 the differentiation of or to interaction with MEF2 a the action of tissue-restricted class MEF2 interaction with or with interaction does not to require class I is by the MEF2/HAND1 synergistic activation of the in which class I of of the in to MEF2/HAND1 activation not the DNA binding of MEF2 sufficient with HAND1 that HAND1 is to transcriptional the MEF2 or activation sufficient HAND1 recruited to DNA by MEF2 and in co-activators or it MEF2 such this it is that the of HAND2 to with the the of MEF2 is known to directly this and it is that HAND1 binding to a MEF2 HAND and HAND1 can to and a The promoter and a a in HAND1 transcriptional does not to in HAND1 results not a or class I in HAND1 transcriptional the and that the of HAND2 that transcriptional activation by HAND proteins interaction with HAND2 a the the by which this that the HAND2 by The to and HAND2 and that HAND2 as a of the protein not the of that HAND1 with it not the promoter or in with results and of that HAND1 is of not cooperativity and HAND1, the MEF2/HAND1 the promoter by the of that MEF2 a interaction not that HAND1 transcription of and that of such as through with transcription and that HAND1 activation of in and the MEF2 or not require the HAND1 or in with MEF2 activation of the promoter in the of that HAND1 can with and MEF2 and transcription via interaction The HAND1 developmental or of the the MEF2 binding to promoter in and as by in this which promoter by in in and MEF2 is and that HAND1 is it is to that HAND1 a MEF2 that to of MEF2 the that HAND1 is a transcriptional and a MEF2 the of MEF2 proteins in and the of including HAND1, are the of the and as HAND1 of the HAND1 in organogenesis and We and members of the

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.