Analysis of the DNA-Binding Profile and Function of TALE Homeoproteins Reveals Their Specialization and Specific Interactions with Hox Genes/Proteins

Penkov, Dmitry; Martin, Daniel; Fernandez-Díaz, Luis C.; Rosselló, Catalina Ana; Torroja, Carlos; Sánchez-Cabo, Fátima; Warnatz, Hans-Jörg; Sultan, Marc; Yaspo, Marie Laure; Gabrieli, Arianna; Tkachuk, Vsevolod A.; Brendolan, Andrea; Blasi, Francesco; Torres, Miguel

doi:10.1016/j.celrep.2013.03.029

Cited by 122 publications

(248 citation statements)

References 74 publications

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“…We identified a total of 5361 Meis1 BSs in the genome and a collection of 3182 genes with a transcription start site (TSS) closest to any Meis1 BS (GEO GSE62786). As previously reported (Penkov et al, 2013), most Meis1 BSs were located in regions remote from their closest associated TSS (Fig. 5A).…”

Section: Microphthalmia Is Not a Consequence Of Meis1 Function In Thesupporting

confidence: 58%

“…5B). When comparing Meis preference for binding to H3K4me1 and H3K4me3 marks, as reported in other tissues (Penkov et al, 2013), we found that Meis1 preferentially binds to enhancer regions (Fig. 5B).…”

Section: Microphthalmia Is Not a Consequence Of Meis1 Function In Thementioning

confidence: 64%

“…5C). The m1 consensus is a very close variant of the Meis1 direct binding sequence identified in the trunk (Penkov et al, 2013), whereas m2-m3 sequences are low-complexity or rather relaxed sequences that we could not correlate to previously described consensus binding motifs.…”

Section: Microphthalmia Is Not a Consequence Of Meis1 Function In Thementioning

confidence: 69%

“…5B). Meis1 selects two main sequences in the embryonic trunk: the Pbx-Hox binding sequence (A/TGATNNAT), to which it binds indirectly, and a direct BS (TGACAG) (Penkov et al, 2013). To determine binding preferences in the developing eye, we identified consensus sequences in the E10.5 eye Meis BS collection.…”

Section: Microphthalmia Is Not a Consequence Of Meis1 Function In Thementioning

confidence: 99%

“…Meis proteins form stable heteromeric complexes with other transcriptional regulators, enhancing their affinity and specificity of binding to DNA sites in the target gene locus (Penkov et al, 2013;Slattery et al, 2011). For example, together with Pbx1, Meis1 plays a major role as a co-factor for the TFs of the Hox complex, which, in turn, have a pivotal and evolutionarily conserved role in orchestrating embryonic trunk development (Duboule, 2007;Mallo and Alonso, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Meis1 coordinates a network of genes implicated in eye development and microphthalmia

et al. 2015

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Microphthalmos is a rare congenital anomaly characterized by reduced eye size and visual deficits of variable degree. Sporadic and hereditary microphthalmos have been associated with heterozygous mutations in genes fundamental for eye development. Yet, many cases are idiopathic or await the identification of molecular causes. Here we show that haploinsufficiency of Meis1, which encodes a transcription factor with evolutionarily conserved expression in the embryonic trunk, brain and sensory organs, including the eye, causes microphthalmic traits and visual impairment in adult mice. By combining analysis of Meis1 loss-offunction and conditional Meis1 functional rescue with ChIP-seq and RNA-seq approaches we show that, in contrast to its preferential association with Hox-Pbx BSs in the trunk, Meis1 binds to Hox/Pbxindependent sites during optic cup development. In the eye primordium, Meis1 coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating genes responsible for human microphthalmia and components of the Notch signaling pathway. In addition, Meis1 is required for eye patterning by controlling a set of eye territory-specific transcription factors, so that in Meis1 −/− embryos boundaries among the different eye territories are shifted or blurred. We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations.

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Section: Microphthalmia Is Not a Consequence Of Meis1 Function In Thesupporting

confidence: 58%

Section: Microphthalmia Is Not a Consequence Of Meis1 Function In Thementioning

confidence: 64%

Section: Microphthalmia Is Not a Consequence Of Meis1 Function In Thementioning

confidence: 69%

Section: Microphthalmia Is Not a Consequence Of Meis1 Function In Thementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Meis1 coordinates a network of genes implicated in eye development and microphthalmia

et al. 2015

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A tale of TALE, PREP1, PBX1, and MEIS1: Interconnections and competition in cancer

et al. 2017

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We report the latest structural information on PREP1 tumor suppressor, the specific ''oncogene'' and ''tumor suppressive'' signatures of MEIS1 and PREP1, the molecular rules regulating PREP1 and MEIS1 binding to DNA, and how these can change depending on the interaction with PBX1, cell-type, neoplastic transformation, and intracellular concentration. As both PREP1 and MEIS1 interact with PBX1 they functionally compete with each other. PREP1, PBX1, and MEIS1 TALE-class homeodomain transcription factors act in an interdependent and integrated way in experimental tumorigenesis. We also pool together the plethora of data available in human cancer databanks and connect them with the available molecular information. The emerging picture suggests that a similarly basic approach might be used to better dissect and define other oncogenes and suppressors and better understand human cancer.

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Hox regulation of transcription: More complex(es)

Ladam

Sagerström

2013

Developmental Dynamics

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Hox genes encode transcription factors with important roles during embryogenesis and tissue differentiation. Genetic analyses initially demonstrated that interfering with Hox genes has profound effects on the specification of cell identity, suggesting that Hox proteins regulate very specific sets of target genes. However, subsequent biochemical analyses revealed that Hox proteins bind DNA with relatively low affinity and specificity. Furthermore, it became clear that a given Hox protein could activate or repress transcription depending on the context. A resolution to these paradoxes presented itself with the discovery that Hox proteins do not function in isolation, but interact with other factors in complexes. The first such “cofactors” were members of the Extradenticle/Pbx and Homothorax/Meis/Prep families. However, the list of Hox-interacting proteins has continued to grow, suggesting that Hox complexes contain many more components than initially thought. Additionally, the activities of the various components and the exact mechanisms whereby they modulate the activity of the complex remain puzzling. Here we review the various proteins known to participate in Hox complexes and discuss their likely functions. We also consider that Hox complexes of different compositions may have different activities and discuss mechanisms whereby Hox complexes may be switched between active and inactive states.

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Analysis of the DNA-Binding Profile and Function of TALE Homeoproteins Reveals Their Specialization and Specific Interactions with Hox Genes/Proteins

Cited by 122 publications

References 74 publications

Meis1 coordinates a network of genes implicated in eye development and microphthalmia

Meis1 coordinates a network of genes implicated in eye development and microphthalmia

A tale of TALE, PREP1, PBX1, and MEIS1: Interconnections and competition in cancer

Hox regulation of transcription: More complex(es)

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