Komal Yasmin

Thank you so much @sproullab.bsky.social 🙏🏻

Thank you Neil,Tatyana& friends@BrockdorffLab @oxfordbiochemistry.bsky.social @wellcometrust.bsky.social for the amazing opportunity
I am truly grateful to @genesdev.bsky.social peer review process which pushed us to dissect the mechanism more deeply which significantly strengthened the paper [12/12

Thank you @Neil,Tatyana& friends@BrockdorffLab @oxfordbiochemistry.bsky.social @wellcometrust.bsky.social for the amazing opportunity.
I am truly grateful to the peer review process which pushed us to dissect the mechanism more deeply & that deeper look significantly strengthened the paper. [12/12]

Residues 146-177 are well conserved in 3B across species. Counterpart in 3A interacts with nucleosomal DNA and histone H2A ubiquitylated at lysine 119 (Chen et al.,2024,Gretarsson et al.2024,and Wapenaar et al. 2024).In 3A it is also proximal to key nucleosome acidic patch interaction site [12A/12]

We expressed a series of small N-terminal deletions to determine any specific subdomain of DNMT3B1 N-terminus required for CGI methylation. While majority of the deletions abrogated CGI methylation, region spanning 146-177 rescued most of 3B-dependent CGI methylation but not on Xi. [11/12]

We then tested the role of unstructured N-terminal domain of DNMT3B in its specificity. Dispensable for the catalytic activity of 3B, this is the least conserved region between 3A and 3B. Expressing N-terminal truncated DNMT3B failed to rescue 3B-dependent CGI methylation [10/12]

We then expressed a chimeric DNMT3B with region spanning PWWP-ADD domains replaced by their equivalent from DNMT3A. Despite being catalytically active, this chimeric protein did not rescue majority of DNMT3B-dependent CGI methylation, indicating key role of these domains in DNMT3B specificity [9/12]

Catalytic domain of DNMT3A & 3B have been implicated in imparting target specificity. We swapped DNMT3B catalytic domain by 3A. This chimeric DNMT3 was able to fully rescue DNNT3B-dependent CGI methylation showing that the catalytic domain doesnt impart specificity to DNMT3B [8/12]

As a putative mechanism of specificity, we tested the contribution of 3B1 & 3B3 in governing specificity by complementing either of two isoform in Dnmt3bKO cells. The complementation of 3B3 did not rescue CGI methylation on Xi or other autosomal DNMT3B-dependent loci [7/12]

Unlike DNMT3A, DNMT3B has various isoforms, many of which are inactive. One isoform, 3B3 has been shown to act as an accessory factor and aid in catalysis of the active isoform 3B1 as well as DNMT3A [6/12]

This experimental system also recapitulated key elements of CGI methylation during development such as specificity of DNMT3B for X-linked CGI methylation and other well reported DNMT3B-dependent loci reported in mouse embryos and in ICF-type1 caused by loss of Dnmt3b function [5/12]

We developed a model system to study CGI methylation during XCI.EB differentiation in female inducible Xist ES cells(iXist-ChrX), followed by MBD-seq proved an excellent system.We captured CGI methylation of developmental loci including germline genes reported in mouse embryos[4/12]

Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X Chromosome What mechanisms contribute to developmental gene regulation and long-term silencing? Gendrel et al. uncover on the inactive X chromosome parallel pathways of slow and fast CpG-island methylation kinet...

We use XCI as a model system to address this question. CGI methylation occurs late in XCI. Previous work from our lab showed that the CGI methylation on Xi is dependent on DNMT3B. However the underlying cause of this specificity is not clear. [3/12]
www.cell.com/developmenta...

While denovo methyltransferases DNMT3A & 3B largely act redundantly to establish CpG methylation, they exhibit specificity for various developmental loci. Dissecting the reason behind this specificity is key to understanding CpG methylation in development & its dysregulation [2/12]

Are you a DNMT3 enthusiast wondering how they achieve specificity at CpG islands during development? And why is DNMT3B specifically required for methylation on the inactive X?

We set out to dissect the mechanism, now published in Genes & Development
genesdev.cshlp.org/content/earl...
[1/12]

I left inspired by the energy and promise in that room, and hopeful that with the right support, these young scientists will take on the world in ways that matter. Their curiosity, resilience, and ambition are powerful. #GivingBack #WomenInScience #STEMPakistan #AcademicJourney #Mentorship #ScienceEducation

Grateful to the University of the Punjab for the warm welcome and the generous recognition.

Scientific talent is universal;access is not. Limited resources & mentorship can make scientific careers harder — something I experienced myself.
Returning to my alma mater reminded me why supporting aspiring scientists matters deeply.
I hope my insights helped students see what’s possible for them.

Thank you so much Duncan. Would've been great to see you there.

Likewise! It was so great to hear your new story. Say hi to all in Oxford.

It was amazing to come to Heidelberg and attend the #EMBLChromatin meeting (after attempting to secure a visa for 3 years!!). Many thought provoking talks and an excellent opportunity to learn, network, and, meet old and new friends. Not too bad getting the poster prize either. 🧬👩🏻‍🔬

A big thanks to the #CRGBIpostdocs organizers for an amazing conference.

It's amazing to be in the sunny Barcelona for #CRGBIpostdocs symposium and to be presenting my postdoc work. Many thanks to the organizers for the excellent opportunity. Great science shared and more to come tomorrow.