Can you believe that until now there were more genomes sequenced for the woolly mammoth than for living African elephants?
Today, we bring you the first genomic, continent-scale analyses of 232 high-quality genomes of both species, the savanna and forest elephant.
www.nature.com/articles/s41...
Don’t miss this thread, then
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Tempted to add Metal gifs; that's how cool METALoci sounds!
In their recent article @natsmb.nature.com, @dariloops.bsky.social @mamartirenom.bsky.social @jrotwitguez.bsky.social @imotagom.bsky.social and colleagues shed light on sex-determining 3D regulatory hubs.
www.nature.com/articles/s41...
The final chapter of my PhD thesis, is finally published in GBE!
academic.oup.com/gbe/article/...
You can also read the earlier recommendation by PCI in a nice little summary here: evolbiol.peercommunityin.org/articles/rec...
#palaeoproteomics #phylogenetics
This conservation genomics course looks great!!
Once again: Why are we letting our world be shaped by such shallow people with no sense of history, culture, creativity or sometimes even logical reasoning?
In summary, METALoci provides novel insights on #sexdetermination, from fundamental mechanisms of #generegulation to their relevance in vivo. (19/19) These and other interesting observations (as well as many Hi-C maps!) can be found in our paper. 🌀🧬 Have a look!
Cheers, sex & rock and roll. 🍻🤘
Top: the top 20 TF regulons for granulosa E13.5 XX (left) and Sertoli E13.5 XY cells (right). Regulons are ranked according to RSS, which is a metric for cell type specificity. Gray small points indicate regulons with mean < 0.3 normalized counts in scRNA-seq, which were discarded for further analysis. Bottom: the top ten positive and negative regulons are indicated. Underlined regulons indicate those factors previously associated with sex determination in the literature. Meis1, which was further investigated in this study, is indicated in blue. B, Gene regulatory network reconstruction for granulosa E13.5 XX (left) and Sertoli E13.5 XY cells (right). Large nodes (circles) represent TFs associated with top regulons (the name of the TF indicated within a white rectangle). The color of the circles represents the expression of the TF, in normalized RNA counts. Small nodes (diamonds) represent target genes (the name is indicated if the gene is a TF). Connecting lines represent TF–gene interactions, with the size of the line being proportional to the weight of the interaction (that is, correlation of expression in scRNA-seq). Red lines correspond to activation and blue lines correspond to repression.
The ovarian marker FOXL2 (green) marks the presence of granulosa cells. Left: testicular marker SOX9 (red) indicates the presence of Sertoli cells. Note the similarities between XY mutants with two deleted Meis alleles (Meis1 homozygous versus Meis1/Meis2double heterozygous), with FOXL2-positive cells located mainly in the gonadal poles (arrowheads). Note also the increase in the number of FOXL2-positive cells (arrowheads) extending across the entire gonads in mutants with three deletedMeis alleles (Meis1 homozygous, Meis2 heterozygous).
METALoci identified Meis1 and Meis2 as redundant, essential regulators of sexual identity in both sexes, acting to stabilise the correct developmental program and prevent inappropriate activation of the opposite-sex pathway. (18/n)
Beyond individual loci, we reconstructed gene regulatory networks repurposing METALoci to work with #scRNA-seq We find lineage-specific regulatory modules (“regulons”), which are transcription factors (TFs) that control gene expression programs in Sertoli ♂️ and granulosa ♀ cells. (17/n)
Importantly, unlike full Fgf9 KO (which causes lung lethality), this regulatory deletion allowed survival.
This uncoupled lung and gonadal phenotypes, highlighting tissue-specific regulatory control. (16/n)
Mutant gonads displayed two distinct phenotypes with different degrees of male-to-female sex reversal, same as in the full Fgf9 knockout.
Immunofluorescence revealed the simultaneous presence of testicular (SOX9) as well as ovarian (FOXL2) and meiotic markers (SYCP3). (15/n)
We identified a non-coding region located approximately 250 Kb downstream of Fgf9, whose deletion was predicted to be disruptive for its regulation.
To validate it, @imotagom.bsky.social and @dariloops.bsky.social generated a #CRISPR homozygous deletion (Δ306) in transgenic mice... (14/n)
What about the potential of METALoci as a predictive tool for regulatory activity? 🧬
We investigated the regulation of Fgf9, a pro-testicular morphogen whose regulation was unknown. (13/n)
METALoci quantifies and compares regulatory activity between samples/conditions. Sox9 transitions from a 3D environment with low activity to a highly active.
We quantified and compared the temporal and sex-specific regulatory activity for all 24,027 genes in the mouse. (12/n)
Using Hi-C and H3K27Ac data, #METALoci reconstructs the 3D enhancer hubs (or "metaloci") for each gene during sex determination.
For example, the testis-specific upregulation of Sox9 is associated with formation of a metaloci (in red) including its two known enhancers, TESCO & Enh13. (11/n)
We specifically repurposed this type of analysis to quantify gene regulation, based on the fact that #enhancers and their target genes may cluster within the 3D nuclear space and display similar #epigenetic properties. (10/n)
No AI slop; just 1950's maths. 🤘🏽😎 #oldschool
In the image, we see a map of the median household income in Paris. Red color indicates areas with high income surrounded by other blocks with similar income. Blue area shows the same for the low income. Pink-ish and light blue, show anti-correlation. (9/n)
#METALoci is based on spatial autocorrelation analysis, classically employed in geostatistics already since the 1950’s, to describe how a variable depends on space at a global and local scales. (8/n)
You might have noticed... I’ve always enjoyed being a metalhead, so didn't miss the opportunity of making a wink to it. 😈 I hope it becomes the “One” and doesn’t “Fade to Black”. (7/n)
Here, we developed and applied METALoci, an unbiased approach to measure and quantify 3D regulatory activity from Hi-C maps. (6/n)
But... 🤔💭:
Are conventional tools for Hi-C analysis well suited to identify meaningful changes for #generegulation?
How can such a minor variation in 3D chromatin organization explain a process characterised by major changes in #transcription and cell identity? (5/n)
Our initial analyses revealed a high degree of conservation in TAD structures and moderate changes in A/B compartments.
3D chromatin structure seems to be mostly preformed before #sexdetermination occurs! (4/n)
Experimental setup of FACS-sorted gonadal populations
In our publication, we explored the 3D regulatory landscape of mammalian #sexdetermination in vivo, combining FACS sorting and low-input Hi-C.
Focusing on the cell lineage initiating this process: bipotential supporting cells that differentiate into granulosa (XX) or Sertoli (XY), in mice. (3/n)
Transgenic mice with XX karyotype when injected with Sry, developed male external genitalia. Koopman et al., 1991: https://www.nature.com/articles/351117a0
The discovery of Sry and the creation of a sex-reversed mouse. (a) Narrowing down of the testis-determining factor from the Y chromosome to the Sry gene. (ZFY: Zinc finger Y-chromosomal gene; SRY: Sex-determining Region of Y chromosome gene). Modified from (McLaren, 1990) and reprinted with permission from Nature. (b) The photo shooting for the cover of Nature was somewhat complicated: (from left to right) Nigel Vivian, Robin Lovell-Badge, and Peter Koopman are trying to get Randy to hang from a rod for the picture. (Image, courtesy of Jérôme Collignon). Image/Diagram adapted from: Stevant et al., 2018 https://www.sciencedirect.com/science/article/pii/S0303720718301230
Mammalian #sexdetermination is directed by the gonad, which can differentiate into ovary or testis. This depends on the presence or absence of a Y chromosome and the SRY gene. Sex-determining signals then induce a physical and behavioural transformation of the entire organism. (2/n)
A sixteenth century woodcut illustrating a statement from an Alexandrian manuscript of the first century AD, stating that if a bull dismounts from the right side of a cow conception will result in a bull calf, whilst descending from the left side will result in a heifer calf. Image extracted and adapted from: Mittwoch, U. Sex determination. EMBO Rep 14, 588–592 (2013). https://doi.org/10.1038/embor.2013.84
Humanity has wondered how sex is determined for more than 2,000 years. It's only in the last century we started to understand the genetic basis of this process. But not much is known about its #epigenetic regulation. (1/n)
But first... a great 👏👏 to our collaborators:
V. Cadenas, S. Dupont, O. Lao, J. Jedamzick, R. Kühn, S. Lacadie, A. Garcia-Moreno, A. Hurtado, M. Torres, F.M. Real, and @rdacemel.bsky.social
🔊💥 How is sex determined? How is it encoded in the #3Dgenome?
Read all about it in our last paper!
www.nature.com/articles/s41...
It’s been looong but feels satisfying to see this finally out.
(With CapelLab, @dariloops.bsky.social Lab and @mamartirenom.bsky.social Lab)
🧵👇
If you are a scientist, working on biology, wondering where to submit your manuscript given the current issues with the academic publishing system, check out wheretopublish.github.io!
We did this thinking change is possible. Let’s make it happen!
the cutoff scores for #MSCA postdoc fellowships are very high this year. has the score distribution shifted compared to previous years? I made a plot with scores from past years.
if scores are at ceiling level, the process becomes essentially a lottery, because minor issues can lead to deductions.
Rereading these two papers:
Holes in the hologenome: why host-microbe symbioses are not holobionts.
journals.asm.org/doi/10.1128/...
The Hologenome Concept: Helpful or Hollow?
journals.plos.org/plosbiology/...
And I still find myself in general agreement with most of the points in them