Kabuki syndrome type 1 and type 2 converge on a shared chromatin and transcriptional state in hiPSC-derived neuroectoderm
This study demonstrates that loss-of-function variants in either KMT2D or KDM6A, which cause Kabuki syndrome types 1 and 2 respectively, converge on a shared chromatin and transcriptional state in human iPSC-derived neuroectoderm characterized by destabilized anterior neural identity and ectopic induction of dorsal, mesenchymal, and sensory programs.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
Kabuki syndrome is a rare condition that affects how a person's body and brain develop before birth. People with this syndrome often have distinctive facial features, heart defects, and intellectual disabilities. For decades, doctors knew the syndrome could be caused by problems in two different genes, named KMT2D and KDM6A. These genes act like specialized workers in a cell's construction crew, helping to manage the chemical tags that tell the body's DNA which parts to use and which to ignore. One gene adds a chemical mark that usually turns genes on, while the other removes a mark that keeps genes off. Even though these two genes perform opposite chemical tasks, they cause very similar problems in people. This has led scientists to wonder if, despite their different jobs, they might be guiding the developing body along the same path. To find out, researchers needed to watch how these cells behave right at the very beginning of life, before they have turned into specific tissues like skin or brain.
A team of scientists set out to watch this early development in a controlled laboratory setting. They started with a single line of human stem cells, which are cells capable of turning into any type of tissue in the body. Using a precise gene-editing tool, they created two new versions of these cells: one with a broken copy of the first gene and another with a broken copy of the second gene. Because they started with the same original cells, the only difference between the two new groups was the specific gene that was broken. The researchers then guided these cells to become neuroectoderm, a group of early cells that will eventually form the brain and nervous system. They stopped the process at a specific point in time, eight days after starting, to take a snapshot of what was happening inside the cells. They measured which genes were active and how open the DNA was to being read, looking for signs of how the cells were changing.
The results showed that the two groups of cells, despite having different broken genes, ended up in almost the same state. The researchers found that hundreds of genes changed their activity in the exact same way in both groups. Some genes that should have been quiet became loud, while others that should have been loud became quiet. When they looked at the physical structure of the DNA, they saw a similar pattern: the regions that control genes became more accessible in some places and less accessible in others, and these changes matched up between the two groups. This suggests that losing either of these two genes leads the cell down the same confusing path, even though the genes themselves do different chemical work.
The cells in both groups showed signs of losing their identity as early brain cells. They stopped expressing the markers that define the front part of the brain, which is crucial for forming the face and the forebrain. Instead, they began to show signs of becoming something else. They started turning on genes associated with the back of the nervous system and with cells that form connective tissue and bone. They also began to express genes that are usually found in sensory nerves. It was as if the cells had forgotten their original plan to become the front of the brain and were instead trying to build a different kind of structure. The researchers also noticed that the cells were turning on a specific set of genes related to sensory perception and peripheral nerves, a group of nine genes that appeared in both types of broken cells.
To understand why this was happening, the scientists looked at the master switches that control these genes, known as transcription factors. These are proteins that bind to DNA to turn genes on or off. They found that in both groups of cells, the proteins that usually keep the brain cells stable were losing their grip. At the same time, a different set of proteins, known as AP-1, was taking over and binding more strongly to the DNA. This new set of proteins seemed to be driving the cells toward the wrong path, activating the genes for connective tissue and sensory nerves while suppressing the genes needed for a healthy brain. The researchers also found that the cells were reacting to a chemical signal called BMP, which is usually involved in forming the back of the body, and that this signal was being turned on too strongly.
The study confirms that even though the two genes involved in Kabuki syndrome perform different chemical tasks, their failure leads to the same developmental error at the earliest stages of brain formation. The cells lose their sense of direction, forgetting to become the front of the brain and instead drifting toward a state that mixes brain, skin, and sensory nerve characteristics. This happens before the cells would normally decide to become specific types of tissue, suggesting that the root of the syndrome lies in this very early confusion. The researchers identified a specific list of 103 genes that are affected in both types of the syndrome, providing a clear target for future studies. While the study does not yet explain how to fix this in patients, it offers a clear map of where the process goes wrong, showing that the two forms of the syndrome are indeed two sides of the same coin.
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