Craniosynostosis–BCL11B Gene Network Node

The flat bones of the mammalian skull and face develop by direct intramembranous ossification of mesenchyme that is principally derived from mesoderm and neural crest cells. Craniofacial sutures are fibrocellular structures that form at the margins of developing bones and limit skull deformation due to both tensile and compressive forces. Craniosynostosis, the premature ossification of cranial sutures, is the most important developmental disorder of the skull vault. Sequelae of this disorder include restricted skull expansion, midfacial hypoplasia, increased intracranial pressure, and craniofacial dysmorphologies, all of which negatively impact respiration, sensory systems, and cognition. We are studying the underlying genetic determinants and molecular mechanisms controlling the maintenance of sutural patency and have identified an essential role for the transcription factor BCL11B in premature fusion of the flat bones of the skull and face. BCL11B interacts directly with the Nucleosome Remodeling and Deacetylation complex (NuRD) and Polycomb-Related Complex 2 (PRC2) through the invariant proteins RBBP4 and RBBP7. We identified a novel, de novo variant in BCL11B, encoding an R3S substitution (p.R3S), in a patient with coronal suture synostosis. The p.R3S substitution occurs within a conserved amino-terminal motif of BCL11B and reduces interaction with both NuRD and PRC2 transcriptional regulatory complexes. The R3S substitution reduces the affinity of BCL11B p.R3S for the RBBP4–MTA1 complex by nearly an order of magnitude. A mouse model of the BCL11B p.R3S substitution recapitulated craniosynostosis of the coronal suture, as well as other cranial sutures. This finding demonstrates that the BCL11B p.R3S substitution is causally associated with craniosynostosis in the identified patient and confirms an important role for BCL11B-regulated gene network in the maintenance of cranial suture patency in humans.

Effect of BCL11B p.R3S substitution on complex bound conformation. RBBP4–MTA1 complex bound structure BCL11B structure of wild-type and p.R3S mutant showing representative equilibrium structures from molecular dynamics simulations.

Tooth Devo

Incisor development in Bcl11b-null mice—Mice lacking the transcription factor BCL11B exhibit severely disrupted ameloblast formation in the developing incisor. BCL11B is a key factor controlling epithelial proliferation and overall developmental asymmetry of the mouse incisor: BCL11B is necessary for proliferation of the labial epithelium and development of the epithelial stem cell niche, which gives rise to ameloblasts; conversely, BCL11B suppresses epithelial proliferation, and development of stem cells and ameloblasts on the inner, or lingual, side of the incisor. This bidirectional action of BCL11B in the incisor epithelia appears responsible for the asymmetry of ameloblast localization in developing incisor. Underlying these spatio-specific functions of BCL11B in incisor development is the regulation of a large gene network comprised of genes encoding several members of the FGF and TGFβ superfamilies, Sprouty proteins, and Sonic hedgehog. Our data integrate BCL11B into these pathways during incisor development and reveal the molecular mechanisms that underlie phenotypes of both Bcl11b–/– and Sprouty mutant mice.


Transcription factors determine which genes are translated into proteins, and when, and thus they serve as the gatekeepers of cellular function. Cell signaling pathways converge on transcription factors, decorating these proteins with an array of post-translational modifications (PTMs) that are often interdependent, being linked in time, space, and combinatorial function. These PTMs orchestrate every activity of a transcription factor over its entire lifespan—from subcellular localization to protein-protein interactions, sequence-specific DNA binding, transcriptional regulatory activity, and protein stability—and play key roles in the epigenetic regulation of gene expression. In this issue, Theresa Filtz, Walter Vogel, and Mark Leid review PTMs most commonly targeting transcription factors, and discuss how PTMs of transcription factors offer numerous potential points of intervention for development of therapeutic.




Cover image concept by Walter Vogel and graphic art by Chris Hunter.

Control of BCL11B transcriptional regulatory activity by post-translational modification

For these studies, we are taking advantage of the natural high abundance and convenient access to a near homogeneous cell population of mouse thymocytes to study the mechanistic linkage between BCL11B post-translational modification (PTMs) and its nuclear effectors and complex partners in this native cell population.

BCL11B is dynamically regulated by multiple PTMs linked to the stimulation of MAPK-mediated signaling pathways. In thymocytes, where BCL11B is critical to three distinct developmental stages, cell surface T Cell Receptor (TCR) activation results in rapid simultaneous phosphophorylation and desumoylation followed by a sequentially linked cycle of dephosphorylation and re-sumoylation. Using tandem mass spectrometry we have directly identified numerous BCL11B phosphorylation sites and the principal sumoylation site, Lysine 679, which was found to be adducted by both the SUMO1 and SUMO2/3. One result of TCR stimulation is the surprisingly complicated linkage between elevated levels SUMO1-BCL11B that recruits the transcriptional co-activator p300 to BCL11B-repressed promoters and the induction of transcription. This appears to operate as BCL11B phospho-deSUMO switch, the basis of which is the phosphorylation-dependent recruitment of the SUMO hyrdrolase SENP1 to phospho-BCL11B, coupled to the hydrolysis of SUMO1-BCL11B. BCL11B acts as part of the Mi2β–NuRD complex and is the substrate of numerous regulated PTM modifying enzymes including the BCL11B phosphatase PP6. We what to identify the key and distinguishing aspects of BCL11B's functional states in terms of PTM status, NuRD complex makeup, and other transcription factors partners.


SUMO1-K679-BCL11B identified in primary mouse thymocytes