A TALE/HOX code unlocks WNT signalling response towards paraxial mesoderm

One fundamental yet unresolved question in biology remains how cells interpret the same signalling cues in a context-dependent manner resulting in lineage specification. A key step for decoding signalling cues is the establishment of a permissive chromatin environment at lineage-specific genes triggering transcriptional responses to inductive signals. For instance, bipotent neuromesodermal progenitors (NMPs) are equipped with a WNT-decoding module, which relies on TCFs/LEF activity to sustain both NMP expansion and paraxial mesoderm differentiation. However, how WNT signalling activates lineage specific genes in a temporal manner remains unclear. Here, we demonstrate that paraxial mesoderm induction relies on the TALE/HOX combinatorial activity that simultaneously represses NMP genes and activates the differentiation program. We identify the BRACHYURY-TALE/HOX code that destabilizes the nucleosomes at WNT-responsive regions and establishes the permissive chromatin landscape for de novo recruitment of the WNT-effector LEF1, unlocking the WNT-mediated transcriptional program that drives NMPs towards the paraxial mesodermal fate.

Neuroendocrine prostate cancer has distinctive, non-prostatic HOX code that is represented by the loss of HOXB13 expression

HOX gene-encoded homeobox proteins control body patterning during embryonic development; the specific expression pattern of HOX genes may correspond to tissue identity. In this study, using RNAseq data of 1019 human cancer cell lines that originated from 24 different anatomic sites, we established HOX codes for various types of tissues. We applied these HOX codes to the transcriptomic profiles of prostate cancer (PCa) samples and found that the majority of prostate adenocarcinoma (AdPCa) samples sustained a prostate-specific HOX code whereas the majority of neuroendocrine prostate cancer (NEPCa) samples did not, which reflects the anaplastic nature of NEPCa. Also, our analysis showed that the NEPCa samples did not correlate well with the HOX codes of any other tissue types, indicating that NEPCa tumors lose their prostate identities but do not gain new tissue identities. Additionally, using immunohistochemical staining, we evaluated the prostatic expression of HOXB13, the most prominently changed HOX gene in NEPCa. We found that HOXB13 was expressed in both benign prostatic tissues and AdPCa but its expression was reduced or lost in NEPCa. Furthermore, we treated PCa cells with all trans retinoic acid (ATRA) and found that the reduced HOXB13 expression can be reverted. This suggests that ATRA is a potential therapeutic agent for the treatment of NEPCa tumors by reversing them to a more treatable AdPCa.

Symmetry Transformations in Metazoan Evolution and Development

In this review, we consider transformations of axial symmetry in metazoan evolution and development, the genetic basis, and phenotypic expressions of different axial body plans. In addition to the main symmetry types in metazoan body plans, such as rotation (radial symmetry), reflection (mirror and glide reflection symmetry), and translation (metamerism), many biological objects show scale (fractal) symmetry as well as some symmetry-type combinations. Some genetic mechanisms of axial pattern establishment, creating a coordinate system of a metazoan body plan, bilaterian segmentation, and left–right symmetry/asymmetry, are analysed. Data on the crucial contribution of coupled functions of the Wnt, BMP, Notch, and Hedgehog signaling pathways (all pathways are designated according to the abbreviated or full names of genes or their protein products; for details, see below) and the axial Hox-code in the formation and maintenance of metazoan body plans are necessary for an understanding of the evolutionary diversification and phenotypic expression of various types of axial symmetry. The lost body plans of some extinct Ediacaran and early Cambrian metazoans are also considered in comparison with axial body plans and posterior growth in living animals.

Loss of HOXB13 expression in neuroendocrine prostate cancer

HOXB13, the most posterior HOX B gene, is primarily expressed in the prostate. Using immunohistochemical staining, we evaluated the expression of HOXB13 in prostatic tissues. We found that HOXB13 was expressed in both benign prostatic tissues and prostate adenocarcinoma (AdPCa) but its expression was reduced or lost in neuroendocrine prostate cancer (NEPCa). Additionally, using RNAseq data of HOXs in cell lines derived from various tissue origins, we established HOX codes for these tissue types. We applied the HOX codes to PCa samples and found that the majority of AdPCa samples sustained the prostate-specific HOX code but the majority of NEPCa samples lost it. Our analysis also showed that the NEPCa samples did not correlate well with the HOX codes of any other tissue type. This indicates that NEPCa tumors lose prostate identity but do not gain a clear-cut new tissue identity. Finally, we treated PCa cells with all trans retinoic acid and found that the reduced/lost HOXB13 expression can be reverted, as can AR and AR targets. Taken together, our data indicate that HOXB13 expression is reduced or lost in NEPCa and a loss of prostate-specific HOX code in NEPCa represents a loss of prostatic identity.

Lin28a/let-7 pathway modulates the Hox code via Polycomb regulation during axial patterning in vertebrates

The body plan along the anteroposterior axis and regional identities are specified by the spatiotemporal expression of Hox genes. Multistep controls are required for their unique expression patterns; however, the molecular mechanisms behind the tight control of Hox genes are not fully understood. In this study, we demonstrated that the Lin28a/let-7 pathway is critical for axial elongation. Lin28a–/– mice exhibited axial shortening with mild skeletal transformations of vertebrae, which were consistent with results in mice with tail bud-specific mutants of Lin28a. The accumulation of let-7 in Lin28a–/– mice resulted in the reduction of PRC1 occupancy at the Hox cluster loci by targeting Cbx2. Consistently, Lin28a loss in embryonic stem-like cells led to aberrant induction of posterior Hox genes, which was rescued by the knockdown of let-7. These results suggest that the Lin28/let-7 pathway is involved in the modulation of the ‘Hox code’ via Polycomb regulation during axial patterning.

Lin28a/let-7 Pathway Modulates the Hox Code via Polycomb Regulation during Axial Patterning in Vertebrates

The body plan along the anteroposterior axis and regional identities are specified by the spatiotemporal expression of Hox genes. Multistep controls are required for their unique expression patterns; however, the molecular mechanisms behind the tight control of Hox genes are not fully understood. In this study, we demonstrated that the Lin28a/let-7 reciprocal regulatory pathway is critical for vertebral specification. Lin28a−/− mice exhibited homeotic transformations of vertebrae which were caused by the global dysregulation of posterior Hox genes. The accumulation of let-7-family microRNAs in Lin28a−/− mice resulted in the reduction of PRC1 occupancy at the Hox cluster loci by targeting Cbx2. Consistently, Lin28a loss in embryonic stem-like cells led to aberrant induction of posterior Hox genes, which was rescued by the knockdown of let-7-family microRNAs. These results suggest that Lin28/let-7 pathway is possibly involved in the modulation of the “Hox code” via Polycomb regulation during axial patterning in vertebrates.