bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2023–10–08
fiveteen papers selected by
Connor Rogerson, University of Cambridge
  1. Hybridization led to a rewired pluripotency network in the allotetraploid Xenopus laevis.
  2. Live-cell imaging uncovers the relationship between histone acetylation, transcription initiation, and nucleosome mobility.
  3. A disordered region controls cBAF activity via condensation and partner recruitment.
  4. An intrinsically disordered region controlling condensation of a circadian clock component and rhythmic transcription in the liver.
  5. Chromatin analysis of adult pluripotent stem cells reveals a unique stemness maintenance strategy.
  6. KaScape: a sequencing-based method for global characterization of protein‒DNA binding affinity.
  7. Elongation roadblocks mediated by dCas9 across human genes modulate transcription and nascent RNA processing.
  8. Structure of histone deacetylase complex Rpd3S bound to nucleosome.
  9. Genome-wide single-molecule analysis of long-read DNA methylation reveals heterogeneous patterns at heterochromatin that reflect nucleosome organisation.
  10. Key transcriptional effectors of the pancreatic acinar phenotype and oncogenic transformation.
  11. Compartmentalization of androgen receptors at endogenous genes in living cells.
  12. TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression.
  13. PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development.
  14. IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia.
  15. Cell layer-specific expression of the homeotic MADS-box transcription factor PhDEF contributes to modular petal morphogenesis in petunia.
  1. Elife. 2023 Oct 03. pii: e83952. [Epub ahead of print]12
    Hybridization led to a rewired pluripotency network in the allotetraploid Xenopus laevis.
    Wesley A Phelps, Matthew D Hurton, Taylor N Ayers, Anne E Carlson, Joel C Rosenbaum, Miler T Lee.
      After fertilization, maternally contributed factors to the egg initiate the transition to pluripotency to give rise to embryonic stem cells, in large part by activating de novo transcription from the embryonic genome. Diverse mechanisms coordinate this transition across animals, suggesting that pervasive regulatory remodeling has shaped the earliest stages of development. Here, we show that maternal homologs of mammalian pluripotency reprogramming factors OCT4 and SOX2 divergently activate the two subgenomes of Xenopus laevis, an allotetraploid that arose from hybridization of two diploid species ~18 million years ago. Although most genes have been retained as two homeologous copies, we find that a majority of them undergo asymmetric activation in the early embryo. Chromatin accessibility profiling and CUT&RUN for modified histones and transcription factor binding reveal extensive differences in predicted enhancer architecture between the subgenomes, which likely arose through genomic disruptions as a consequence of allotetraploidy. However, comparison with diploid X. tropicalis and zebrafish shows broad conservation of embryonic gene expression levels when divergent homeolog contributions are combined, implying strong selection to maintain dosage in the core vertebrate pluripotency transcriptional program, amid genomic instability following hybridization.
    Keywords:  developmental biology; evolutionary biology; xenopus
    DOI:  https://doi.org/10.7554/eLife.83952
  2. Sci Adv. 2023 Oct 06. 9(40): eadh4819
    Live-cell imaging uncovers the relationship between histone acetylation, transcription initiation, and nucleosome mobility.
    Matthew N Saxton, Tatsuya Morisaki, Diego Krapf, Hiroshi Kimura, Timothy J Stasevich.
      Histone acetylation and RNA polymerase II phosphorylation are associated with transcriptionally active chromatin, but their spatiotemporal relationship in live cells remains poorly understood. To address this problem, we combine Fab-based labeling of endogenous protein modifications with single-molecule tracking to quantify the dynamics of chromatin enriched with histone H3 lysine-27 acetylation (H3K27ac) and RNA polymerase II serine-5 phosphorylation (RNAP2-Ser5ph). Our analysis reveals that chromatin enriched with these two modifications is generally separate. In these separated sites, we show that the two modifications are inversely correlated with one another on the minutes time scale and that single nucleosomes within each region display distinct and opposing dynamics on the subsecond time scale. While nucleosomes diffuse ~15% faster in chromatin enriched with H3K27ac, they diffuse ~15% slower in chromatin enriched with RNAP2-Ser5ph. These results argue that high levels of H3K27ac and RNAP2-Ser5ph are not often present together at the same place and time, but rather each marks distinct transcriptionally poised or active sites, respectively.
    DOI:  https://doi.org/10.1126/sciadv.adh4819
  3. Cell. 2023 Sep 29. pii: S0092-8674(23)00965-0. [Epub ahead of print]
    A disordered region controls cBAF activity via condensation and partner recruitment.
    Ajinkya Patil, Amy R Strom, Joao A Paulo, Clayton K Collings, Kiersten M Ruff, Min Kyung Shinn, Akshay Sankar, Kasey S Cervantes, Tobias Wauer, Jessica D St Laurent, Grace Xu, Lindsay A Becker, Steven P Gygi, Rohit V Pappu, Clifford P Brangwynne, Cigall Kadoch.
      Intrinsically disordered regions (IDRs) represent a large percentage of overall nuclear protein content. The prevailing dogma is that IDRs engage in non-specific interactions because they are poorly constrained by evolutionary selection. Here, we demonstrate that condensate formation and heterotypic interactions are distinct and separable features of an IDR within the ARID1A/B subunits of the mSWI/SNF chromatin remodeler, cBAF, and establish distinct "sequence grammars" underlying each contribution. Condensation is driven by uniformly distributed tyrosine residues, and partner interactions are mediated by non-random blocks rich in alanine, glycine, and glutamine residues. These features concentrate a specific cBAF protein-protein interaction network and are essential for chromatin localization and activity. Importantly, human disease-associated perturbations in ARID1B IDR sequence grammars disrupt cBAF function in cells. Together, these data identify IDR contributions to chromatin remodeling and explain how phase separation provides a mechanism through which both genomic localization and functional partner recruitment are achieved.
    Keywords:  ARID1A; ARID1B; ATP-dependent chromatin remodeling; IDRs; cBAF complexes; condensates; intrinsically disordered regions; mammalian SWI/SNF complexes; phase separation; transcription factors
    DOI:  https://doi.org/10.1016/j.cell.2023.08.032
  4. Mol Cell. 2023 Oct 05. pii: S1097-2765(23)00705-0. [Epub ahead of print]83(19): 3457-3469.e7
    An intrinsically disordered region controlling condensation of a circadian clock component and rhythmic transcription in the liver.
    Kun Zhu, Isaac J Celwyn, Dongyin Guan, Yang Xiao, Xiang Wang, Wenxiang Hu, Chunjie Jiang, Lan Cheng, Rafael Casellas, Mitchell A Lazar.
      Circadian gene transcription is fundamental to metabolic physiology. Here we report that the nuclear receptor REV-ERBα, a repressive component of the molecular clock, forms circadian condensates in the nuclei of mouse liver. These condensates are dictated by an intrinsically disordered region (IDR) located in the protein's hinge region which specifically concentrates nuclear receptor corepressor 1 (NCOR1) at the genome. IDR deletion diminishes the recruitment of NCOR1 and disrupts rhythmic gene transcription in vivo. REV-ERBα condensates are located at high-order transcriptional repressive hubs in the liver genome that are highly correlated with circadian gene repression. Deletion of the IDR disrupts transcriptional repressive hubs and diminishes silencing of target genes by REV-ERBα. This work demonstrates physiological circadian protein condensates containing REV-ERBα whose IDR is required for hub formation and the control of rhythmic gene expression.
    Keywords:  3D genome; REV-ERB; circadian; condensates; intrinsically disordered region; liver; repression; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.010
  5. Sci Adv. 2023 Oct 06. 9(40): eadh4887
    Chromatin analysis of adult pluripotent stem cells reveals a unique stemness maintenance strategy.
    Axel Poulet, Arcadia J Kratkiewicz, Danyan Li, Josien C van Wolfswinkel.
      Many highly regenerative organisms maintain adult pluripotent stem cells throughout their life, but how the long-term maintenance of pluripotency is accomplished is unclear. To decipher the regulatory logic of adult pluripotent stem cells, we analyzed the chromatin organization of stem cell genes in the planarian Schmidtea mediterranea. We identify a special chromatin state of stem cell genes, which is distinct from that of tissue-specific genes and resembles constitutive genes. Where tissue-specific promoters have detectable transcription factor binding sites, the promoters of stem cell-specific genes instead have sequence features that broadly decrease nucleosome binding affinity. This genic organization makes pluripotency-related gene expression the default state in these cells, which is maintained by the activity of chromatin remodelers ISWI and SNF2 in the stem cells.
    DOI:  https://doi.org/10.1126/sciadv.adh4887
  6. Sci Rep. 2023 Oct 03. 13(1): 16595
    KaScape: a sequencing-based method for global characterization of protein‒DNA binding affinity.
    Hong Chen, Yongping Xu, Jianshi Jin, Xiao-Dong Su.
      It is difficult to exhaustively screen all possible DNA binding sequences for a given transcription factor (TF). Here, we developed the KaScape method, in which TFs bind to all possible DNA sequences in the same DNA pool where DNA sequences are prepared by randomized oligo synthesis and the random length can be adjusted to a length such as 4, 5, 6, or 7. After separating bound from unbound double-stranded DNAs (dsDNAs), their sequences are determined by next-generation sequencing. To demonstrate the relative binding affinities of all possible DNA sequences determined by KaScape, we developed three-dimensional KaScape viewing software based on a K-mer graph. We applied KaScape to 12 plant TF family AtWRKY proteins and found that all AtWRKY proteins bound to the core sequence GAC with similar profiles. KaScape can detect not only binding sequences consistent with the consensus W-box "TTGAC(C/T)" but also other sequences with weak affinity. KaScape provides a high-throughput, easy-to-operate, sensitive, and exhaustive method for quantitatively characterizing the relative binding strength of a TF with all possible binding sequences, allowing us to comprehensively characterize the specificity and affinity landscape of transcription factors, particularly for moderate- and low-affinity binding sites.
    DOI:  https://doi.org/10.1038/s41598-023-43426-x
  7. Nat Struct Mol Biol. 2023 Oct 02.
    Elongation roadblocks mediated by dCas9 across human genes modulate transcription and nascent RNA processing.
    Inna Zukher, Gwendal Dujardin, Rui Sousa-Luís, Nick J Proudfoot.
      Non-cleaving Cas9 (dCas9) is widely employed to manipulate specific gene loci, often with scant regard for unintended transcriptional effects. We demonstrate here that dCas9 mediates precise RNA polymerase II transcriptional pausing followed by transcription termination and potential alternative polyadenylation. By contrast, alternative splicing is unaffected, likely requiring more sustained alteration to elongation speed. The effect on transcription is orientation specific, with pausing only being induced when dCas9-associated guide RNA anneals to the non-template strand. Targeting the template strand induces minimal effects on transcription elongation and thus provides a neutral approach to recruit dCas9-linked effector domains to specific gene regions. In essence, we evaluate molecular effects of targeting dCas9 to mammalian transcription units. In so doing, we also provide new information on elongation by RNA polymerase II and coupled pre-mRNA processing.
    DOI:  https://doi.org/10.1038/s41594-023-01090-9
  8. Nat Struct Mol Biol. 2023 Oct 05.
    Structure of histone deacetylase complex Rpd3S bound to nucleosome.
    Wulong Li, Hengjun Cui, Zhimin Lu, Haibo Wang.
      Crosstalk between histone modifications represents a fundamental epigenetic mechanism in gene regulation. During the transcription elongation process, the histone deacetylase complex Rpd3S is recruited to H3K36-methylated nucleosomes to suppress cryptic transcription initiation. However, how subunits of Rpd3S are assembled and coordinated to recognize nucleosomal substrates and exert their deacetylation function remains unclear. Here we report the structure of Saccharomyces cerevisiae Rpd3S deacetylase bound to H3K36me3-modified nucleosome at 3.1 Å resolution. It shows that Sin3 and Rco1 subunits orchestrate the assembly of the complex and mediate its contact with nucleosome at multiple sites, with the Sin3-DNA interface as a pivotal anchor. The PHD1 domain of Rco1 recognizes the unmodified H3K4 and places the following H3 tail toward the active site of Rpd3, while the chromodomain of Eaf3 subunit recognizes the H3K36me3 mark and contacts both nucleosomal and linker DNA. The second copy of Eaf3-Rco1 is involved in neighboring nucleosome binding. Our work unravels the structural basis of chromatin targeting and deacetylation by the Rpd3S complex.
    DOI:  https://doi.org/10.1038/s41594-023-01121-5
  9. PLoS Genet. 2023 Oct 02. 19(10): e1010958
    Genome-wide single-molecule analysis of long-read DNA methylation reveals heterogeneous patterns at heterochromatin that reflect nucleosome organisation.
    Lyndsay Kerr, Ioannis Kafetzopoulos, Ramon Grima, Duncan Sproul.
      High-throughput sequencing technology is central to our current understanding of the human methylome. The vast majority of studies use chemical conversion to analyse bulk-level patterns of DNA methylation across the genome from a population of cells. While this technology has been used to probe single-molecule methylation patterns, such analyses are limited to short reads of a few hundred basepairs. DNA methylation can also be directly detected using Nanopore sequencing which can generate reads measuring megabases in length. However, thus far these analyses have largely focused on bulk-level assessment of DNA methylation. Here, we analyse DNA methylation in single Nanopore reads from human lymphoblastoid cells, to show that bulk-level metrics underestimate large-scale heterogeneity in the methylome. We use the correlation in methylation state between neighbouring sites to quantify single-molecule heterogeneity and find that heterogeneity varies significantly across the human genome, with some regions having heterogeneous methylation patterns at the single-molecule level and others possessing more homogeneous methylation patterns. By comparing the genomic distribution of the correlation to epigenomic annotations, we find that the greatest heterogeneity in single-molecule patterns is observed within heterochromatic partially methylated domains (PMDs). In contrast, reads originating from euchromatic regions and gene bodies have more ordered DNA methylation patterns. By analysing the patterns of single molecules in more detail, we show the existence of a nucleosome-scale periodicity in DNA methylation that accounts for some of the heterogeneity we uncover in long single-molecule DNA methylation patterns. We find that this periodic structure is partially masked in bulk data and correlates with DNA accessibility as measured by nanoNOMe-seq, suggesting that it could be generated by nucleosomes. Our findings demonstrate the power of single-molecule analysis of long-read data to understand the structure of the human methylome.
    DOI:  https://doi.org/10.1371/journal.pgen.1010958
  10. PLoS One. 2023 ;18(10): e0291512
    Key transcriptional effectors of the pancreatic acinar phenotype and oncogenic transformation.
    Ana Azevedo-Pouly, Michael A Hale, Galvin H Swift, Chinh Q Hoang, Tye G Deering, Jumin Xue, Thomas M Wilkie, L Charles Murtaugh, Raymond J MacDonald.
      Proper maintenance of mature cellular phenotypes is essential for stable physiology, suppression of disease states, and resistance to oncogenic transformation. We describe the transcriptional regulatory roles of four key DNA-binding transcription factors (Ptf1a, Nr5a2, Foxa2 and Gata4) that sit at the top of a regulatory hierarchy controlling all aspects of a highly differentiated cell-type-the mature pancreatic acinar cell (PAC). Selective inactivation of Ptf1a, Nr5a2, Foxa2 and Gata4 individually in mouse adult PACs rapidly altered the transcriptome and differentiation status of PACs. The changes most emphatically included transcription of the genes for the secretory digestive enzymes (which conscript more than 90% of acinar cell protein synthesis), a potent anabolic metabolism that provides the energy and materials for protein synthesis, suppressed and properly balanced cellular replication, and susceptibility to transformation by oncogenic KrasG12D. The simultaneous inactivation of Foxa2 and Gata4 caused a greater-than-additive disruption of gene expression and uncovered their collaboration to maintain Ptf1a expression and control PAC replication. A measure of PAC dedifferentiation ranked the effects of the conditional knockouts as Foxa2+Gata4 > Ptf1a > Nr5a2 > Foxa2 > Gata4. Whereas the loss of Ptf1a or Nr5a2 greatly accelerated Kras-mediated transformation of mature acinar cells in vivo, the absence of Foxa2, Gata4, or Foxa2+Gata4 together blocked transformation completely, despite extensive dedifferentiation. A lack of correlation between PAC dedifferentiation and sensitivity to oncogenic KrasG12D negates the simple proposition that the level of differentiation determines acinar cell resistance to transformation.
    DOI:  https://doi.org/10.1371/journal.pone.0291512
  11. Nucleic Acids Res. 2023 Oct 04. pii: gkad803. [Epub ahead of print]
    Compartmentalization of androgen receptors at endogenous genes in living cells.
    Selçuk Yavuz, Hélène Kabbech, Jente van Staalduinen, Simon Linder, Wiggert A van Cappellen, Alex L Nigg, Tsion E Abraham, Johan A Slotman, Marti Quevedo, Raymond A Poot, Wilbert Zwart, Martin E van Royen, Frank G Grosveld, Ihor Smal, Adriaan B Houtsmuller.
      A wide range of nuclear proteins are involved in the spatio-temporal organization of the genome through diverse biological processes such as gene transcription and DNA replication. Upon stimulation by testosterone and translocation to the nucleus, multiple androgen receptors (ARs) accumulate in microscopically discernable foci which are irregularly distributed in the nucleus. Here, we investigated the formation and physical nature of these foci, by combining novel fluorescent labeling techniques to visualize a defined chromatin locus of AR-regulated genes-PTPRN2 or BANP-simultaneously with either AR foci or individual AR molecules. Quantitative colocalization analysis showed evidence of AR foci formation induced by R1881 at both PTPRN2 and BANP loci. Furthermore, single-particle tracking (SPT) revealed three distinct subdiffusive fractional Brownian motion (fBm) states: immobilized ARs were observed near the labeled genes likely as a consequence of DNA-binding, while the intermediate confined state showed a similar spatial behavior but with larger displacements, suggesting compartmentalization by liquid-liquid phase separation (LLPS), while freely mobile ARs were diffusing in the nuclear environment. All together, we show for the first time in living cells the presence of AR-regulated genes in AR foci.
    DOI:  https://doi.org/10.1093/nar/gkad803
  12. Nat Commun. 2023 Oct 04. 14(1): 6185
    TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression.
    Elizabeth Heyes, Anna S Wilhelmson, Anne Wenzel, Gabriele Manhart, Thomas Eder, Mikkel B Schuster, Edwin Rzepa, Sachin Pundhir, Teresa D'Altri, Anne-Katrine Frank, Coline Gentil, Jakob Woessmann, Erwin M Schoof, Manja Meggendorfer, Jürg Schwaller, Torsten Haferlach, Florian Grebien, Bo T Porse.
      The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPADM AML are GATA2 and TET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPADM AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.
    DOI:  https://doi.org/10.1038/s41467-023-41927-x
  13. Nat Commun. 2023 09 30. 14(1): 6119
    PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development.
    Hwee Hui Lau, Nicole A J Krentz, Fernando Abaitua, Marta Perez-Alcantara, Jun-Wei Chan, Jila Ajeian, Soumita Ghosh, Yunkyeong Lee, Jing Yang, Swaraj Thaman, Benoite Champon, Han Sun, Alokkumar Jha, Shawn Hoon, Nguan Soon Tan, Daphne Su-Lyn Gardner, Shih Ling Kao, E Shyong Tai, Anna L Gloyn, Adrian Kee Keong Teo.
      The coding variant (p.Arg192His) in the transcription factor PAX4 is associated with an altered risk for type 2 diabetes (T2D) in East Asian populations. In mice, Pax4 is essential for beta cell formation but its role on human beta cell development and/or function is unknown. Participants carrying the PAX4 p.His192 allele exhibited decreased pancreatic beta cell function compared to homozygotes for the p.192Arg allele in a cross-sectional study in which we carried out an intravenous glucose tolerance test and an oral glucose tolerance test. In a pedigree of a patient with young onset diabetes, several members carry a newly identified p.Tyr186X allele. In the human beta cell model, EndoC-βH1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content, and altered hormone gene expression. Deletion of PAX4 in human induced pluripotent stem cell (hiPSC)-derived islet-like cells resulted in derepression of alpha cell gene expression. In vitro differentiation of hiPSCs carrying PAX4 p.His192 and p.X186 risk alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content that can be reversed with gene correction. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function, and its contribution to T2D-risk.
    DOI:  https://doi.org/10.1038/s41467-023-41860-z
  14. Nat Commun. 2023 09 30. 14(1): 6117
    IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia.
    Ke Zheng, Nannan Sha, Guofang Hou, Zhuyun Leng, Qin Zhao, Li Zhang, Lingnan He, Meidong Xu, Yuhui Jiang, Tao Chen.
      The proline synthesis is importantly involved in tumor growth under hypoxia, while the underlying mechanism remains to be further investigated. Here we show that pyrroline-5-carpoxylate reductase-1 (PYCR1), displaying a constant nuclear localization, is phosphorylated by nuclear IGF1R at Tyrosine 135 under hypoxia; this phosphorylation promotes the binding of PYCR1 to ELK4 and thus PYCR1 recruitment to ELK4-targeted genes promoter. Under hypoxia, ELK4-binding ability and enzymatic activity of PYCR1 are both required for ELK4-Sirt7-mediated transcriptional repression and cell growth maintenance, in which PYCR1-catalyzed NAD+ production stimulates the deacetylation activity of Sirt7 on H3K18ac that restrains genes transcription. Functionally, PYCR1 Tyr-135 phosphorylation exerts supportive effect on tumor growth under hypoxia, and the level of PYCR1 Tyr-135 phosphorylation is associated with malignancy of colorectal cancer (CRC). These data uncover the relationship between the compartmentally metabolic activity of PYCR1 and genes transcription regulation, and highlight the oncogenic role of PYCR1 during CRC development.
    DOI:  https://doi.org/10.1038/s41467-023-41658-z
  15. Plant Cell. 2023 Oct 06. pii: koad258. [Epub ahead of print]
    Cell layer-specific expression of the homeotic MADS-box transcription factor PhDEF contributes to modular petal morphogenesis in petunia.
    Mathilde Chopy, Quentin Cavallini-Speisser, Pierre Chambrier, Patrice Morel, Jérémy Just, Véronique Hugouvieux, Suzanne Rodrigues Bento, Chloe Zubieta, Michiel Vandenbussche, Marie Monniaux.
      Floral homeotic MADS-box transcription factors ensure the correct morphogenesis of floral organs, which are organized in different cell layers deriving from distinct meristematic layers. How cells from these distinct layers acquire their respective identities and coordinate their growth to ensure normal floral organ morphogenesis is unresolved. Here, we studied petunia (Petunia x hybrida) petals that form a limb and tube through congenital fusion. We identified petunia mutants (periclinal chimeras) expressing the B-class MADS-box gene DEFICIENS in the petal epidermis or in the petal mesophyll, called wico and star, respectively. Strikingly, wico flowers form a strongly reduced tube while their limbs are almost normal, while star flowers form a normal tube but greatly reduced and unpigmented limbs, showing that petunia petal morphogenesis is highly modular. These mutants highlight the layer-specific roles of PhDEF during petal development. We explored the link between PhDEF and petal pigmentation, a well-characterized limb epidermal trait. The anthocyanin biosynthesis pathway was strongly down-regulated in star petals, including its major regulator ANTHOCYANIN2 (AN2). We established that PhDEF directly binds to the AN2 terminator in vitro and in vivo, suggesting that PhDEF might regulate AN2 expression and therefore petal epidermis pigmentation. Altogether, we show that cell layerspecific homeotic activity in petunia petals differently impacts tube and limb development, revealing the relative importance of the different cell layers in the modular architecture of petunia petals.
    DOI:  https://doi.org/10.1093/plcell/koad258
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