We recently reported that promoter competition can contribute to the robust insulation of gene regulatory domains (www.nature.com/articles/s41...).
We now offer a 4-years PhD contract to investigate whether the dirsuption of this regulatory mechanism can lead to congenital defects. More details 👇

OFERTA DE EMPLEO (por favor difundir):

Ofrecemos un contrato predoctoral de 4 años asociado a nuestro proyecto PID2024-157249OB-I00. El objetivo del proyecto es evaluar un nuevo mecanismo patológico según el cual la competición entre promotores puede llegar a ocasionar enfermedades congénitas
👇

Lastly, by deleting a few MLL2-bound L1 elements, we demonstrated that these elements act as enhancers of MLL2 target genes in both ESC and upon differentiation

In agreement with this possibility, Micro-C experiments revealed that MLL2-bound L1 elements engaged into physical contacts with the promoters of nearby MLL2 target genes and such interactions were slightly decreased in the absence of MLL2

Interestingly, the genes downregulated in the absence of MLL2 were significantly closer to MLL2-bound L1 elements than to either upregulated or unaffected genes (especially upon ESC differentiation)

In the absence of MLL2, the 5’UTR of the MLL2-bound L1 elements lost not only H3K4me3, but also H3K27ac, while gaining H3K9me3 but not H3K27me3. Therefore, MLL2 controls the activity of a subset of L1 elements in both pluripotent and differentiating cells

It turned out that the majority of those MLL2-bound distal CpG-poor regions (distal -) corresponded to the CG-rich 5’UTR of young LINE1 elements belonging preferentially to the L1Md_T, L1Md_A and L1Md_Gf subfamilies

So, how can MLL2 control gene expression then?

Upon inspection of our MLL2 ChIP-seq data, we were surprised to find out that, in addition to many CpG-rich promoters, MLL2 was also bound to a large number of distal CpG-poor regions, where it also controlled H3K4me3 levels

Moreover, although MLL2 was bound to many bivalent promoters where it controlled H3K4me3 levels, the loss of MLL2 barely increased PRC1 or PRC2 levels at those promoters

However, by combining conditional MLL1/2 KO cell lines with ChIP-seq and RNA-seq, we found that, in the absence of MLL2, only a small fraction of the differentially expressed genes in either pluripotent or differentiating cells corresponded to developmental genes with bivalent promoters

Instead, our data suggest that the emergent regulatory properties of enhancer clustering preferentially entail a strong increase in RNA Pol II pause release and elongation and, thus, in the fraction of enhancer-promoter contacts that are transcriptionally productive

As previously reported for super-enhancers, the 4x enhancer cluster synergistically increased the expression of its target gene. However, this could not be explained by changes in enhancer-promoter contact frequency or the formation of transcriptional condensates

The addition of a CTCF binding site (CBS) to the “core“ enhancer stalled cohesin and generated a smaller sub-domain/chromatin hub. However, despite these clear insulatory effects, enhancer-promoter contacts and, most importantly, target gene expression were barely affected by the CBS

To do so, we generated transgenic mESC lines in which different types of synthetic enhancers (i.e. “typical” enhancer, CTCF-associated enhancer, 4x enhancer cluster) were built upon the same “core” enhancer and inserted at the same distance from a developmental gene (i.e. 100 Kb from Gata6)

Enhancers are a heterogeneous group of cis-regulatory elements with diverse genetic architectures and regulatory properties. However, previous studies often examined them under variable conditions, which makes it challenging to disentangle the unique regulatory properties of each enhancer type

Do you have an exciting story about #enhancers or #enhanceropathies?. Then submit your abstract to the @embo.org workshop on "Enhancer mechanics and Enhanceropathies" in Denmark before is too late: the deadline for abstract submissions is in two weeks (March 17th)!

meetings.embo.org/event/25-enh...

Birding in Santoña

Fulfilling a family tradition the day before Christmas. Hike to la Picota #Cantabria

Thanks @joadelas.bsky.social for visiting us and sharing your exciting projects with us. You , @jcacosta.bsky.social and Silvia Remeseiro did a great job during María’s defense.